Semisynthesis of Bioactive Compounds and their Biological Activities 9780443152696

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SEMISYNTHESIS OF BIOACTIVE COMPOUNDS AND THEIR BIOLOGICAL ACTIVITIES

SEMISYNTHESIS OF BIOACTIVE COMPOUNDS AND THEIR BIOLOGICAL ACTIVITIES SASADHAR MAJHI Department of Chemistry (UG & PG Department), Trivenidevi Bhalotia College, Raniganj, West Bengal, India

SIVAKUMAR MANICKAM Petroleum and Chemical Engineering Department, University of Technology Brunei, Brunei Darussalam

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright Ó 2024 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-443-15269-6 For information on all Elsevier publications visit our website at https://www.elsevier.com/books-and-journals Publisher: Candice Janco Acquisitions Editor: Gabriela Capille Editorial Project Manager: Anthony Marvullo Production Project Manager: Rashmi Manoharan Cover Designer: Miles Hitchen Typeset by TNQ Technologies

Contents 1. Preliminary concept of semisynthesis and its importance 1.1

Introduction 1.1.1 Concept of semisynthesis 1.1.2 Why do we need semisynthesis? 1.1.3 Recent advances in the potential applications of semisynthetic derivatives 1.1.4 Relationship between semisynthesis and drug delivery References

2. Semisynthesis of antibiotics 2.1 2.2

Current antibiotic resistance mechanism Chemical derivatization of antibiotics 2.2.1 Semisynthesis of platencin thioether derivatives 2.2.2 Semisynthesis of dialkylresorcinol derivatives 2.2.3 Semisynthesis of unguinol derivatives 2.2.4 Semisynthesis of arsinothricin 2.2.5 Semisynthesis of fidaxomicin derivatives 2.2.6 Semisynthesis of amidochelocardin derivatives 2.2.7 Semisynthesis of nidulin derivatives 2.2.8 Semisynthesis of teicoplanin derivatives 2.2.9 Semisynthesis of platensimycin derivatives 2.2.10 Semisynthesis of glycopeptides 2.2.11 Semisynthesis of lipopeptides 2.2.12 Semisynthesis of caprazene derivatives 2.3 Recent advances in the clinical applications of antibiotics and their analogs References

3. Semisynthesis of alkaloids 3.1

3.2

Function of plant alkaloids on human health 3.1.1 Anticancer activity of plant alkaloids 3.1.2 Antimicrobial activity of plant alkaloids Semisynthetic modification of alkaloids 3.2.1 Semisynthesis of apetalrine B 3.2.2 Semisynthesis of promising derivatives of the verticillin class of natural products

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3.2.3

Semisynthesis of promising derivatives of rutaecarpine and evodiamine 3.2.4 Semisynthesis of (þ)- and ()-spondomine and stereoisomers 3.2.5 Semisynthesis of esters of galanthamine, 3-O-methylpancracine, vittatine, and maritidine 3.2.6 Semisynthesis of brevicanines A and B 3.2.7 Semisynthesis of 15-chloro-18-oximinoether derivatives 3.2.8 Semisynthesis of 2-epi-narciclasine 3.2.9 Semisynthesis of acetylated makaluvamines 3.2.10 Semisynthesis of the analogs of maclekarpine E 3.2.11 Semisynthesis of (þ)-goniomitine 3.2.12 Semisynthesis of piperine-based hydrazone derivatives 3.2.13 Semisynthesis of lipo-alkaloids 3.2.14 Semisynthesis of oxystemofoline, methoxystemofoline and analogs 3.3 Semisynthesis of bioactive marine alkaloids 3.3.1 Semisynthesis of N12-acetylpseudoceratidine, N12-formylpseudoceratidine, N-methylpseudoceratidine and pseudoceratidine azido derivatives 3.3.2 Semisynthesis of antitumor drug Ecteinascidin 743 and ()-Jorumycin 3.3.3 Semisynthesis of monoamines derivative 3.3.4 Semisynthesis of discorhabdins P and U and analogs of discorhabdin C 3.4 Recent progress in semisynthesis and potential applications of semisynthetic alkaloid derivatives References

4. Semisynthesis of flavones 4.1

68 69 70 71 73 74 76 77 78 79 80 80 82

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Spectral characteristics of flavonoids 113 00 4.1.1 Luteolin 7-O-(4 -caffeoyl) b-D-glucopyranoside (1) 113 4.1.2 6,600 ,3000 - trihydroxy-7,30 ,700 -O-trimethylloniflavone (2) 116 4.1.3 Lineaflavones AD (3e6), 6-methoxygeraldone (7), 800 -acetylobovatin (8), and 5-hydroxy-7-methoxysaniculamin A (9) 118 4.1.4 Flavonol glucoside cyclodimer (10) 120 4.1.5 Rac-6-formyl-5,7-dihydroxyflavanone (11) 127 4.1.6 Acacetin-7-O-[b-D-glucopyranosyl(10000 /200 )-4000 -O-acetyl-a-Lrhamnopyranosyl(1000 /600 )]-b-D-glucopyranoside (12), acacetin-7-O[60000 -O-acetyl-b-Dglucopyranosyl(10000 /200 )-3000 -O-acetyl-a-Lrhamnopyranosyl(1000 /600 )]-b-D-glucopyranoside (13) and acacetin-7O-[30000 ,60000 -di-O-acetyl-b-D-glucopyranosyl(10000 /200 )-4000 -O-acetyla- L - rhamnopyranosyl(1000 /600 )]-b-D-glucopyranoside (14) 129

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4.1.7 4.1.8 4.1.9

Afzelin A (15) (2R,3R)-200 -acetyl astilbin (16) (þ)-500 -deacetylpurpurin (17), (þ)-5-methoxypurpurin (18), (2S)-2,3-dihydrotephroglabrin (19), and (2S)-2,3-dihydroteph roapollin C (20) 4.1.10 Aquisiflavoside (21) 4.2 Chemical derivatization of flavonoids 4.2.1 Semisynthesis of flavone hybrids 4.2.2 Semisynthesis of natural flavonoids and flavonoid glycosides 4.2.3 Semisynthesis of chafuroside B, a C-glycosylated bioactive flavone 4.2.4 Semisynthesis of kaempferol-based antimicrobial agents 4.2.5 Semisynthesis of methyl ether derivatives of quercetin 4.2.6 Semisynthesis of 5,7-dihydroxy-3,6-dimethoxy-2(4-methoxyphenyl)-4H-chromen-4-one and 5-hydroxy-3,7dimethoxy-2-(4-methoxyphenyl)-4H-chromen-4-one 4.2.7 Semisynthesis of 5-hydroxy-3,7-dimethoxy-2-(4-methoxyphenyl)4H-chromen-4-one and 5-hydroxy-3,6,7-trimethoxy-2-(4methoxyphenyl)-4H-chromen-4-one 4.2.8 Semisynthesis of 6,8-dibromogenkwanin 4.2.9 Semisynthesis of icaritin-based antibiotics 4.2.10 Semisynthesis of 5,7,40 -triacetoxy jaceosidin, 5,7,40 tripivaloyloxy jaceosidin, and 5,7,40 -trimethoxy jaceosidin 4.2.11 Semisynthesis of acetylated and methylated derivatives of flavonoids 4.2.12 Semisynthesis of polymethoxyflavonoids 4.2.13 Semisynthesis of 5,30 -dihydroxy-3,6,7,8,40 pentamethoxyflavone, casticin, gossypetin 3,7,8,40 -tetramethyl ether, 5,7,30 -trihydroxy-3,6,8,40 -tetramethoxyflavone, 8dimethylaminocasticin 4.3 Chemistry and biological activities of flavonoids and their analogs 4.3.1 Chemistry of flavonoids 4.3.2 Biological activities of flavonoids and their analogs References

5. Semisynthesis of lignans 5.1 5.2

Gastrointestinal tract metabolism of lignans in humans Chemical derivatization of lignans

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135 138 140 140 143 143 145 146

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5.2.1

Semisynthesis of bursehernin and matairesinol dimethyl ether derivatives 5.2.2 Semisynthesis of aminomethylated obovatol derivatives 5.2.3 Semisynthesis of benzoxazole and benzoxazolone derivatives 5.2.4 Semisynthesis of furofuran lignans 5.2.5 Semisynthesis of 9-norlignans 5.2.6 Semisynthesis of cubebin derivatives 5.2.7 Semisynthesis of arylnaphthalene lignan derivatives 5.2.8 Semisynthesis of schisantherin A analogs 5.2.9 Semisynthesis of podophyllotoxin derivatives 5.2.10 Semisynthesis of 4a-arylsulfonyloxybenzyloxy2b-chloropodophyllotoxin derivatives 5.3 Recent developments in the bioactivities of semisynthetic lignan analogs 5.3.1 Anticancer activity of semisynthetic lignan analogs 5.3.2 Estrogenic activity of semisynthetic lignan analogs 5.3.3 Insecticidal activity of semisynthetic lignan analogs 5.3.4 Antimicrobial activity of semisynthetic lignan analogs References

6. Semisynthesis of phenolic compounds 6.1

6.2 6.3

Merits of ultrasound-assisted extraction of phenolic compounds 6.1.1 The mechanism of ultrasound-assisted extraction of phenolic compounds 6.1.2 Ultrasound-assisted extraction of phenolic compounds Microwave-assisted extraction of phenolic compounds Chemical derivatization of phenolic compounds 6.3.1 Semisynthesis of racemic and enantiomerically pure chiral juncuenin B derivatives 6.3.2 Semisynthesis of lecanoric acid, atranorin, norlobaridone, and orsellinic acid derivatives 6.3.3 Semisynthesis of thymol, carvacrol, guaiacol, and eugenol derivatives 6.3.4 Semisynthesis of hydroxytyrosol u-hydroxyalkylcarbonate derivatives and hydroxytyrosol alkylcarbonate derivatives 6.3.5 Semisynthesis of prenylated resveratrol derivatives 6.3.6 Semisynthesis of ferulic acid derivatives 6.3.7 Semisynthesis of barbatusol, demethylsalvicanol, and rosmaridiphenol 6.3.8 Semisynthesis of (5Z)-7-oxozeaenol analogues 6.3.9 Semisynthesis of oleacein from oleuropein

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6.3.10 Semisynthesis of novel derivatives of natural guttiferone-A (LFQM-79, LFQM-80, LFQM-81, LFQM-82, LFQM-113 and LFQM-114) 6.4 Recent advances in the bioactivities of semisynthetic derivatives of phenolic compounds 6.4.1 Anticancer activity of semisynthetic derivatives of phenolic compounds 6.4.2 Antimicrobial activity of semisynthetic derivatives of phenolic compounds 6.4.3 Antioxidant activity of semisynthetic derivatives of phenolic compounds 6.4.4 Semisynthetic derivatives of phenolic compounds as efficient feed additives 6.4.5 Neuroprotective activity of semisynthetic derivatives of phenolic compounds References

7. Semisynthesis of anthocyanins 7.1 7.2 7.3

7.4

Anthocyanins as food colorants and additives The effect of pH on the chemical structure of anthocyanins Chemical derivatization of anthocyanins 7.3.1 Semisynthesis of stearic ester derivatives 7.3.2 Semisynthesis of type A vitisins and type B vitisins 7.3.3 Semisynthesis of pyranomalvidin-3-glucoside-(þ)-catechin pigment 7.3.4 Semisynthesis of [30 -O-methyl-3H]malvidin-3-glucoside 7.3.5 Semisynthesis of anthocyanin-pyruvic acid adducts A-D 7.3.6 Semisynthesis of methyl pyranoanthocyanin 7.3.7 Semisynthesis of oxovitisins 7.3.8 Semisynthesis of methylated cyanidin-3-O-glucoside derivatives 7.3.9 Semisynthesis of cyanidin 3-(600 -benzoyl)-glucoside, cyanidin 3-(600 -salicyloyl)-glucoside and cyanidin 3-(600 -cinnamoyl)glucoside 7.3.10 Semisynthesis of cyanidin-3-glucoside-fatty acid lipophilic derivatives 7.3.11 Semisynthesis of 5-methylpyranopelargonidin and 4-methylfuropelargonidin Anticancer activities of anthocyanidins and their derivatives 7.4.1 Lung cancer 7.4.2 Breast cancer

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7.4.3 7.4.4 7.4.5 7.4.6 References

Colorectal cancer Prostate cancer Ovarian cancer Skin cancer

8. Semisynthesis of natural products at room temperature 8.1 8.2

Room-temperature chemical transformations: a concept Chemical derivatization of natural products at room temperature 8.2.1 Davis oxidation or Davis oxaziridine oxidation at room temperature 8.2.2 Michael addition reaction at room temperature 8.2.3 Norrish type II reaction at room temperature 8.2.4 Photosantonin rearrangement at room temperature 8.2.5 Sharpless epoxidation at room temperature 8.2.6 Oxa-StorkDanheiser reaction at room temperature 8.2.7 Semisynthesis of ()-bufospirostenin A using Wilkinson’s catalyst at room temperature 8.2.8 Semisynthesis of lignan derivatives at room temperature 8.2.9 Semisynthesis of steroid derivatives at room temperature 8.2.10 Semisynthesis of terpenoids derivatives at room temperature 8.2.11 Semisynthesis of xanthones at room temperature 8.3 Potential agricultural biotechnology applications of semisynthetic derivatives References

9. Semisynthesis of natural products under greener conditions 9.1 9.2

9.3

Concept of sustainability Semisynthesis of natural products using green tools 9.2.1 Semisynthesis of CRV431 using flow chemistry as a green tool 9.2.2 Semisynthesis of natural products using microwave irradiation as a green tool 9.2.3 Semisynthesis of natural products using ultrasound as a green tool 9.2.4 Semisynthesis of natural products using visible light as a green tool Semisynthesis of natural products using water as a green solvent 9.3.1 Semisynthesis of thymol-based 1,2,3-triazole hybrids 9.3.2 Semisynthesis of selenoauraptene 9.3.3 Semisynthesis of a cotylenin A mimic

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9.3.4 Semisynthesis of novel matrine derivatives 9.4 Sustainability of natural products as a drug resource 9.5 Targeted microbial transformations References

10. Semisynthesis of natural products through the insertion of oxygen atom under metal-free conditions 10.1 Concept of toxicity 10.2 Merits of metal-free reactions 10.3 Semisynthesis of different natural products via insertion of the oxygen atom 10.3.1 Semisynthesis using molecular oxygen (O2) 10.3.2 Semisynthesis using ozone (O3) 10.3.3 Semisynthesis using hydrogen peroxide (H2O2) 10.3.4 Semisynthesis using dimethyldioxirane (DMDO) 10.3.5 Semisynthesis using 2-iodoxybenzoic acid (IBX) 10.3.6 Semisynthesis using m-CPBA References

11. Adaptation of organic reactions in the industrial production of bioactive compounds 11.1 Cholesterol-lowering drug 11.1.1 Atorvastatin calcium 11.1.2 A green-by-design biocatalytic procedure for the synthesis of atorvastatin intermediate 11.2 Analgesic drug 11.2.1 Opiates 11.3 Antimalarial drug 11.3.1 Artemisinin and its derivatives 11.3.2 Simplified and efficient synthesis of artesunate 11.4 Anti-influenza 11.4.1 Oseltamivir phosphate 11.5 Inhibitory neurotransmitter 11.5.1 Pregabalin 11.6 Anticancer drug 11.6.1 TaxolÒ 11.7 Miscellaneous 11.7.1 Preparation of acylated triterpenes (oleanolic acid and maslinic acid) from olive-oil industry wastes References

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12. New derivatives as nutraceuticals: regulatory considerations 12.1 Nutraceuticals 12.2 Regulatory Aspects 12.2.1 Terminologies, classifications, and preliminary concepts 12.2.2 Regulatory aspects in the United States of America 12.2.3 Regulatory aspects in the European Commission 12.2.4 Regulatory aspects in New Zealand 12.2.5 Regulatory aspects in Australia 12.2.6 Regulatory aspects in Japan 12.2.7 Regulatory aspects in China 12.2.8 Regulatory aspects in India 12.2.9 Regulatory aspects in Canada References

13. Computational chemistry of natural product analogues 13.1 13.2 13.3

Binding studies Molecular modeling Spectroscopic and X-ray analysis of active sites 13.3.1 Spectral properties of stigmasterol 13.3.2 Infrared absorption spectrum of stigmasterol 13.3.3 1H-NMR, 13C-NMR and DEPT-135 spectra of stigmasterol 13.3.4 Computational methods 13.4 Strategies in biological assessment 13.5 Molecular networking 13.6 Machine learning for target identification and synthesis 13.7 High throughput automated synthesis and testing 13.7.1 Application of high-throughput experimentation 13.8 An overview of existing databases and their use in rational drug design 13.8.1 Challenges associated with traditional drug design 13.8.2 Rational drug design 13.9 Repurposing of targeted drugs 13.10 Network pharmacology 13.11 3D printing of reactionware (additive manufacturing) References

14. Developing semisynthesis methods for neglected tropical diseases

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14.1 Brief overview of neglected tropical diseases (NTDs) 439 14.2 Development of semisynthesis methods for neglected tropical diseases 440

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14.2.1 14.2.2 14.2.3 14.2.4 14.2.5 14.2.6 14.2.7 14.2.8 14.2.9 14.2.10 14.2.11 14.2.12 References Index

Semisynthesis of p-quinone analog containing komaroviquinone pharmacophore Semisynthesis of N-aryl amide analogs of piperine Semisynthesis of cryptolepine analogs Semisynthesis of dolabellane analogs Semisynthesis of methyl dehydrodieugenol B Semisynthesis of hederagenin methyl ester analogs Semisynthesis of thiazinoquinone analogue thiazoavarone Semisynthesis of dehydrodieugenol B and methyldehydrodieugenol B derivatives Semisynthesis of lupeol derivatives Semisynthesis of quinoline derivatives Semisynthesis of aphidicolin derivatives Semisynthesis of betulin and betulinic acid derivatives

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CHAPTER ONE

Preliminary concept of semisynthesis and its importance 1.1 Introduction 1.1.1 Concept of semisynthesis Natural products have historically played an important role in drug discovery and development, especially in treating cancer and infectious diseases [1,2]. Natural products are mainly featured by various scaffolds, structural complexity, higher molecular rigidity, and significant pharmacological properties [3,4]. Further, they typically possess a higher molecular mass, more oxygen atoms, a greater number of sp3 carbon atoms, and a few halogen atoms [5]. A greater degree of hydrophilicity as well as minor calculated octanol-water partition coefficients, the presence of stereogenic centers, and the existence of H-bond donors and acceptors than that of synthetic compound libraries make natural products both advantageous and provocative for drug discovery [6,7]. Besides, natural products have a greater rigidity that can be superior in drug invention tackling proteinprotein interactions [8]. Secondary metabolites are important for drug development as Mother Nature has favored and maintained compounds with a high affinity for binding to biological structures [9]. A few drawbacks of natural products have led pharmaceutical companies to reduce natural product-based drug discovery programs despite their many merits and several successful drug discovery instances. For example, several bioactive natural products are not obtained sufficiently from natural sources, especially from higher plants and marine organisms [10]. The isolation and characterization of complex bioactive secondary metabolites may also be challenging [11]. Therefore, semisynthesis is necessary to create new compounds with distinct chemical and medicinal properties from natural products as lead structures [12]. As natural products are rarely used directly in clinical applications in their original forms, they were a good starting point for the design and synthesis of analogs [13]. In order to create novel compounds with diverse pharmacological activities, a semisynthesis or partial chemical Semisynthesis of Bioactive Compounds and their Biological Activities ISBN: 978-0-443-15269-6 https://doi.org/10.1016/B978-0-443-15269-6.00011-0

© 2024 Elsevier Inc. All rights reserved.

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synthesis is necessary [12,14]. Semisynthetic derivatives are frequently preferred due to their enhanced activity or toxicity profiles [15]. It is necessary to chemically derivatize many secondary metabolites to improve their therapeutic window, pharmacokinetic properties, and stability [12e14]. Structural modifications of natural products and secondary metabolites are crucial in several cases. Modern research disclosed that semisynthetic derivatives are valuable sources of novel drug candidates with diverse pharmacological properties [5,16,17]. Living organisms are great chemical factories that can construct structurally-complex secondary metabolites by biosynthesis through enzymatic reactions. Natural product derivatives are typically generated by hybrid processes combining organic synthesis and biosynthesis [15]. Especially, development in different types of sp3 CeH bond functionalization reactions, ring-forming reactions, and skeletal rearrangement processes have gifted to the reappearance of semisynthesis as an effective strategy for synthesizing structurally-complex biologically active molecules of natural origin [18]. Several drugs on the market are of natural origin with structural modifications, as the molecules of natural origin are chemically tailored and modified based on the structural and biological characteristics of the molecules. There has been a dramatic increase in molecular-level syntheses and modifications during the drug revolution [19]. Statistically, natural products and their semisynthetic derivatives accounted for 25% of all new drugs approved between 1981 and 2014 [20]. Based on scientific evidence, between 1981 and 2014, 73% of approved anticancer compounds and 65% of approved antibacterial compounds were natural products or derivatives [20,21]. A significant share (21%) of the contribution is accounted for by semisynthetic derivatives [12]. Semisynthesis has been proven to be a practical method to generate natural product pharmaceuticals, and semisynthesis aims to enhance selectivity, therapeutic action, and patentability [5,12]. Incorporating halogen atoms and improving lipophilicity are excellent modifications that enhance biological properties [5,12,16,17]. Compared to total synthesis, semisynthesis requires fewer steps in preparing various medicines. Using semisynthesis in large-scale anticancer drug production is exemplified by preparing paclitaxel TaxolÒ) from 10-deacetylbaccatin III by introducing the acetyl group and necessary sidechain by a series of steps [22,23]. Using microbially-derived artemisinic acid as the synthetic precursor, large-scale production of the antimalarial drug artemisinin has been achieved [24e27]. The chemical derivatization of natural products is the only practical method for studying structure-activity relationships (SARs),

Preliminary concept of semisynthesis and its importance

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a relationship between a compound’s chemical structure and its biological activity or desired property [12]. According to the Dictionary of Natural Products [28], approximately 200,000 plant secondary metabolites have been identified, covering approximately 170,000 unique structures. Interestingly, approximately 15% of drug interventions are associated with plants [12,14,29]. Plant species are still largely unexplored in drug discovery campaigns. So far, less than 1% of bacterial species, less than 5% of fungi, and 5e15% of the 250,000 species of higher plants (terrestrial flora) have been chemically and pharmacologically explored. Thus, most natural resources are unrecognized [30e32]. Consequently, faithful drives are necessary to explore nature as a source of active phytochemicals that may act as the leads and scaffolds for improving novel drugs. As a result, semisynthesis would be an effective method for exploring natural sources as lead compounds in the synthesis and design of their analogs, which plays an important role in drug discovery and development [12]. For researchers, students, and the next generations, the concept of semisynthesis will be beneficial and suitable for accumulating knowledge regarding structural modifications of natural products for developing new medicines for the community in the future. Natural products are physicochemically similar to normal medicinal chemistry principles applied to semisynthetic compounds in that they simplify drug discovery since the physicochemical properties of natural products to simplify drug discovery are no different compared to normal medicinal chemistry principles applied to semisynthetic compounds.

1.1.2 Why do we need semisynthesis? This section discusses the need for semisynthesis to improve the biological properties of parent natural products and enhance the therapeutic window of these products [12,14]. Neurodegenerative disorders are characterized by the unavoidable loss of a specific type of neuron. Several neurodegenerative disorders, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and spinal muscular atrophy, exemplify this phenomenon [33]. In the United States, severe and chronic neurodegenerative diseases account for 13% of deaths annually and are responsible for an economic burden of approximately $300 billion annually [34]. It is common for neurodegenerative diseases to cause tissue damage due to programmed cell death. As cells in the central nervous system have limited

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Semisynthesis of Bioactive Compounds and their Biological Activities

regenerative capabilities, this tissue damage is irreversible. Neurodegenerative diseases are drug-poor and therefore have limited access to clinically accepted therapeutics. Several studies have shown that the natural diterpenoid serofendic acid provides neuroprotection against mechanisms of cell death associated with this disease. It is highly potent and shows neuroprotective effects at nanomolar concentrations [35]. Serofendic acid has demonstrated promising results in preclinical studies, but its development has been limited due to the lack of an adaptable source for this animalderived natural product. Fetal calf serum contains trace amounts of serofendic acid (3.1 mg per 250 L) [36]. Due to eight chiral carbon centers and four fused rings, the total synthesis is probably slow and inefficient, and yields are low (around 1%) [37e40]. Thus, a sustainable and effective method of providing diterpenoid serofendic acid is urgently needed. As a result, we require a semisynthesis of serofendic acid since few drugs can effectively treat neurodegenerative diseases [41]. In 2019, the natural neuroprotective compound serofendic acid was semisynthesized from ent-atiserenoic acid (1) by Smanski et al. (Fig. 1.1) [41], using an engineered bacterium that produces it (Chapter 8, Scheme 8.1) [38]. In drug discovery and development, natural products and their analogs have improved chemotherapy [6]. Several pharmaceutical products are derived from natural products that have been structurally modified [19,42]. Between 1981 and 2014, 73% of approved anticancer molecules were natural products or their derivatives [20,21]. The verticillins, a class of epipolythiodioxopiperazine alkaloids, have demonstrated potent cytotoxicity [43]. The epipolythiodioxopiperazine alkaloid verticillin A (2) demonstrated potent antitumor activity against various cancer cell lines [44]. As a result of the relatively low availability of this alkaloid 2 through culture from natural sources, its development has been hindered. Hence, semisynthesis plays an important role in overcoming the limitations of verticillin A (2) and related compounds, particularly their poor solubility and optimization to investigate the structure-activity relationship (SAR) through structural modification of the C11 hydroxy group. Several semisynthetic derivatives of the verticillin type of natural products were synthesized by Oberlies et al. in 2021, and their antiproliferative activities were evaluated against melanoma, ovarian, and breast cancer cell lines [45]. Some acylated verticillin H derivatives were more effective than the parent compound verticillin H (3). As verticillins have limited solubility, adding these groups may increase their drug properties, such as cell permeability [44]. In addition, little research has been conducted on their mode of binding. The bridged

Preliminary concept of semisynthesis and its importance

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Fig. 1.1 Chemical structures of the starting natural products as lead compounds.

disulfide moiety has been identified as the critical characteristic of SARs [46]. Adding these acyl substituents does not affect these groups or reduce activity against cancer cell lines in this case. A conformational change in the molecule was induced by acylation, as evidenced by the different reactivity of C11 and C110 alcohols (Chapter 3, Scheme 3.2). As a result of natural menopause occurring at a mean age of 49 years [47e49], hormone replacement therapy (HRT) or menopausal hormone therapy is used to treat symptoms associated with menopause. Estrone, equilenin, and equilin are the components of Premarin tablets used as hormone replacement therapy to treat symptoms and conditions associated with menopause [50]. Because there is no effective synthetic method for equilenin and equilin these substances are still extracted from the urine of pregnant

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mares. At the same time, estrone is synthesized on an industrial scale by chemical synthesis. Premarin contains three active ingredients that are derivatives of equilenin [51]. Due to economic and technical considerations, equilenin and its derivatives cannot be synthesized on an industrial scale by total synthesis [52,53]. On the other hand, semisynthesis is undoubtedly more practical for producing large quantities of equilenin from inexpensive starting materials, such as 19-hydroxyandrost-4-ene-3,17-dione (4), because equilenin and its derivatives are crucial intermediates in the preparation of steroidal drugs [50]. A practical semisynthesis of the estrogenic steroid equilenin and its derivatives was developed by Ding and co-workers in 2016 using 19-hydroxyandrost-4-ene-3,17-dione (4) as a starting material (Chapter 8, Scheme 8.11) [50]. It is well known that plants are susceptible to various diseases caused by pathogenic fungi. It has been estimated that phytopathogenic fungi cause an annual economic loss of more than $200 billion due to quality decline and decreased crop yields [54]. As well as posing a threat to food safety, plant pathogenic fungi produce mycotoxins that can harm humans and animals [55,56]. Various synthetic chemical plant fungicides have been widely used in modern agricultural systems to control mycosis in plants. As a result of the persistent and excessive application of chemical fungicides over the past decades, serious health and environmental problems have occurred. A novel fungicide that is both effective and selective, as well as eco-friendly, is required to protect Mother Nature [57]. Plant-derived botanical protectants have recently gained much attention due to their low environmental impact and mammalian toxicity [58]. As a result of semisynthesis, it is possible to develop fungicides based on natural products and with new structural skeletons [59]. From natural lignan obovatol (5), Cao et al. produced several Mannich base derivatives with potential antifungal activity by modifying them with C-4-aminomethyl groups in 2020 (Chapter 5, Scheme 5.2) [60]. An antibiotic is a medicine that prevents and treats bacterial infections. The development of antibiotic resistance occurs when certain groups of germs become resistant to these drugs over time [61]. Antimicrobial resistance is among the greatest threats to human and animal health, food security, and community development [62]. In 2019, it was estimated that 1.27 million deaths were directly caused by antimicrobial resistance, while 4.95 million deaths were estimated to be caused by antimicrobial resistance [63]. Due to antibiotic resistance, new analogues are needed with enhanced biological and pharmacological activities and improved safety profiles [64].

Preliminary concept of semisynthesis and its importance

7

Semisynthesis is the most practical method of obtaining new analogues in quantities that can be used in clinical trials. Clark et al. synthesized a series of analogues of natural dialkylresorcinol 2-hexyl-5-pentylresorcinol (6) and examined their antibacterial activity [65]. Compared to the parent compound 6, the mono-halogenated derivatives displayed similar activity. Conversely, the monofluorosulfated derivative exhibited greater activity against S. aureus and S. epidermidis, with MIC values of 1.1 and 2.1 mg mL1, respectively (Chapter 2, Scheme 2.2). The main active ingredient of Pithecellobium clypearia Benth is a natural flavonoid known as 7-O-galloyltricetiflavan (7) [66]. This flavonoid contains seven phenolic hydroxyl groups and is known for its anti-oxidant and neuroprotective properties, which have been linked to preventing Alzheimer’s disease [67]. However, like most natural flavonoids, 7-O-galloyltricetiflavan (7) possesses several pharmacochemical disadvantages, such as low bioavailability and significant instability; high instability is caused primarily by oxidation of the polyphenolic groups [68]. Therefore, it is essential to modify 7-O-galloyltricetiflavan (7) to improve its stability and bioavailability to enhance its efficacy in treating Alzheimer’s disease. To enhance the bioavailability of 7-O-galloyltricetiflavan (7) scaffolds for the design of anti-Alzheimer agents, Song and co-workers methylated the phenolic hydroxyl groups in 2020 (Chapter 4, Scheme 4.1) [69]. Lanthipeptides are known as lantibiotics; Gram-positive bacteria produce them as a defense mechanism against other species of bacteria and are ribosomal synthesized from lanthionine-containing bactericidal peptides [70]. There are challenges associated with chemical approaches, including total synthesis [71], for the preparation of lantibiotics and their analogues [72,73] with additional desirable properties because of the complex structures of the lantibiotics, namely nisin (8). The peptide nature of nisin (8) also poses some limitations, including susceptibility to proteolytic degradation in vivo, weak pharmacokinetics, and toxicity [74]. Using a semisynthesis, lantibiotics with desirable properties may be synthesized from a naturally occurring compound. As an alternative method of producing semisynthetic lipopeptides from natural bacteriocin nisin (8), Martin and colleagues have developed derivatives that are antibacterially active and proteolytically stable (Chapter 2, Scheme 2.13) [75]. Several synthesized derivatives inhibited the growth of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) strains tested with activity similar to that of the parent antibacterial peptide nisin (8). Due to their unique lipid II-assisted mode of action and superior stability to nisin (8), semisynthetic

8

Semisynthesis of Bioactive Compounds and their Biological Activities

lipopeptides are attractive candidates for further development as new antibiotics (Fig. 1.1) [75]. Furthermore, stereoselectivity can be achieved through semisynthesis. Using epi-androsterone (9) as a starting material, Br€ase et al. performed the first stereoselective semisynthesis of natural cardenolides uzarigenin and allo-uzarigenin in 2023 [76].

1.1.3 Recent advances in the potential applications of semisynthetic derivatives Cao and co-workers reported the semisynthesis and biological investigation of some new Mannich base derivatives as promising antifungal agents from natural lignan obovatol (5) as a lead compound in 2020 [60]. Different phytopathogenic fungi were tested for antifungal activity in vitro using the spore germination and mycelium growth rate methods [76]. The semisynthetic derivatives tested showed varying levels of inhibition against the four fungal spores. Derivatives 10a and 10b demonstrated broad-spectrum and potential inhibitory effects on three fungal spores (Fig. 1.2). Compared to two positive controls, hymexazol and difenoconazole, compounds 10a and 10b showed higher inhibition of Botrytis cinerea spore germination with IC50 values of 28.68 and 16.90 mg/mL, respectively. The derivatives 10b and 10c were less potent than positive controls and exhibited IC50 values of 63.19 and 83.80 mg/mL, respectively, against A. solani. The derivatives 10b, 10d, and 10e inhibited Botrytis cinerea mycelial growth by greater than 90% at concentrations of 100 mg/mL [60]. According to the World Health Organization, cancer is the second leading cause of death worldwide, accounting for approximately 1.7 million new cancer cases in the United States alone in 2019 and 9.6 million deaths, or one in six deaths worldwide in 2018 [77]. The cancer burden continues to grow worldwide, exerting enormous emotional, physical, and financial stress on individuals, families, societies, and health systems. Treating certain types of cancer, such as triple-negative breast and ovarian cancer, remains challenging [78]. There is still a need for drug invention and improvement efforts to address this burden. Several semisynthetic analogs of the drug, including ixabepilone [79], taxotere [80], topotecan [81], and irinotecan (also called CPT-11) [82], have been approved by the FDA for the treatment of cancer. From natural verticillin A (2) as starting material, Fuchs and coworkers synthesized nine semisynthetic derivatives (11e19) bearing ester, carbamate, carbonate, and sulfonate functionalities of the verticillin class of natural products in 2021 [45]. Several semisynthetic analogs were tested

Preliminary concept of semisynthesis and its importance

9

Fig. 1.2 Chemical structures of semisynthetic derivatives with promising biological activities.

for their ability to inhibit breast, melanoma, and ovarian cancer cell lines. The IC50 values of all analogs were found to be in the nanomolar range, close to, and in some cases, stronger than those of their parent compounds [45]. Plants have provided significant anticancer leads, including podophyllotoxin, paclitaxel, camptothecin, and vinblastine, which are shown to have remarkable anticancer properties [83e85]. These lead compounds have been modified chemically through semisynthesis to produce structural analogs with higher pharmacological activity and fewer side effects [86]. Teniposide, etoposide, and etopophos, which are semisynthetic derivatives of podophyllotoxin, act as inhibitors of topoisomerase II [42]. Docetaxel is a semisynthetic analog of paclitaxel that acts as an inhibitor of microtubulin [87]. Topotecan and irinotecan, modified forms of camptothecin, are anticancer agents that inhibit topoisomerase I [88,89]. Several semisynthetic natural product derivatives are being studied in clinical trials, including matecan, alvocidib, phenoxodiol, and fosbratabulin [90,91]. Nazreena et al. synthesized 1,2,3-triazoles based on thymol and evaluated their anticancer potential in MDA-MB-231 and MCF-7 cancer cells [92]. Among the synthesized hybrids, compound 20 showed the most potent cytotoxicity (IC50 6.17 mM), which is similar to tamoxifen (sold under the brand

10

Semisynthesis of Bioactive Compounds and their Biological Activities

name Nolvadex) (IC50 5.62 mM) and showed a 3.2 fold inhibition to 5-fluorouracil with an IC50 value of 20.09 mM against MCF-7 cancer cells. In contrast, compounds 20 (IC50 10.52 mM) and 21 (IC50 11.41 mM) exhibited 1.42 and 1.3 fold inhibition, respectively, to tamoxifen (Nolvadex) (IC50 15.01 mM) and 2.4 fold along with 2.2 activity to 5-fluorouracil (IC50 25.31 mM) (Chapter 9, Scheme 9.8). It has been widely recognized that selenium-containing compounds possess important pharmacological activities, including antioxidant and anticancer properties [93]. Selenium-based drugs have demonstrated promise as orally active treatments for conditions such as hypertension, infections, cancer, and immune system suppression in various diseases [94]. Ebselen, a synthetic organoselenium drug molecule, is known for mimicking glutathione peroxidase [95]. As a result, most efforts have been devoted to developing pure synthetic compounds containing Se, while less attention has been paid to naturally occurring semisynthetic compounds containing Se. The bioactive monoterpene geranyloxycoumarin auraptene has been isolated from Aegle marmelos and Citrus aurantium [96]. Structure-based analogs of auraptene are an exciting area of research with potential outcomes and applications shortly [97]. As a key step in their method, Epifano and coworkers performed the semisynthesis of selenoauraptene (22) from natural 7-hydroxycoumarin in 2021 (Fig. 1.2) [98] (Chapter 9, Scheme 9.9). Table 1.1 provides an overview of recent advances in the biological activity of some semisynthetic derivatives.

1.1.4 Relationship between semisynthesis and drug delivery Drug delivery systems (DDS) are devices or formulations for delivering pharmaceutical compounds selectively to their target sites without damaging non-target cells, organs, or tissues [122]. Drug delivery refers to the delivery of a therapeutic substance to achieve a therapeutic effect in humans or animals; it describes the process by which drugs are delivered into or throughout the body. In various pharmaceutical industries, micelles or nanoparticles serve as drug carriers [123]; they protect the drug from degradation and enable it to reach where it is needed in the body. Although drug delivery systems have improved, oral administration of therapeutic agents is still challenging. Due to their exceptional properties, semisynthetic biopolymer complexes are nanocarriers for oral drug delivery. The properties of natural polymers, namely biocompatibility, are combined with those of synthetic polymers, namely good thermal and mechanical

Starting natural product (class)

Annonalide (diterpenoid) Callitrisic acid (diterpenoid) CDCHD (2carboxamido-2deacetyl-chelocardin) (antibiotic) Columbin (diterpenoid) Honokiol (neolignan) Hydroxytyrosol (phenol) Kirenol (diterpenoid) Lupeol (triterpenoid) Macrocarpal A (diterpenoid) Mangiferin (xanthone)

Source (family)

Semisynthetic derivatives

Bioactivity of semisynthetic derivatives

References

Casimirella (icacinaceae)

Nine analogs

Antitumor

[99]

Callitris columellaris F. Muell (Cupressaceae) Amycolatopsis sulphurea (Pseudonocardiaceae)

Jiadifenoic acid C

Antiviral

[100]

Twenty-two analogs

Antibacterial

[101]

Jateorhiza columba (Menispermaceae) Magnolia officinalis (Magnoliaceae) Olive oil (Oleaceae)

Eight analogs

KOR (kappa-opioid receptor) activity Insecticidal

[102]

Siegesbeckia orientalis (Compositae) Bombax ceiba (Bombacaceae) Eucalyptus globulus (Myrtaceae) Gentiana asclepiadea L. (Gentianaceae)

Thirty-seven analogs Ten analogs

[103] [104]

Seven analogs

Trypanocidal and cytotoxic FXa inhibition

Five analogs

Skin recovery activity

[106]

Macrocarpal C

Antibacterial and antiviral Hypoglycemic

[107]

Neomangiferin

Preliminary concept of semisynthesis and its importance

Table 1.1 Developments in the biological activities of semisynthetic derivatives.

[105]

[108]

11

(Continued)

Starting natural product (class)

Source (family)

Semisynthetic derivatives

Sophora alopercuroides L. (Fabaceae)

Sophocarpine

Maslinic acid (triterpenoid) Morelloflavone (flavonoid)

Olea europaea L. (Oleaceae) Garcinia Brasiliensis (Guttiferae)

Seven triazole analogs

Narciclasine (alkaloid)

Narcissus pseudonarcissus (Amaryllidaceae) Magnolia obovata Thunb (Fabaceae) Olea europaea (Fabaceae) Cnidium monnieri (Apiaceae) Mallotus philippensis (Euphorbiaceae) Uncaria rhynchophylla (Rubiaceae) Trichilia connaroides (Meliaceae) Soybean (Fabaceae)

Obovatol (lignan) Oleuropein (phenol) Ostiole (coumarin) Rottlerin (phenol) Saponin A (saponin) Secotrichagmalin (triterpenoid) Tocopherol (vitamin)

Three derivatives

Antinociceptive, anticancer, and antiinflammatory Herbicide

References

[109]

[110] [111]

2-epi narciclasine, narciprimine Twenty-one analogs

Leishmanicidal, antiproteolytic, antioxidant activities and low cytotoxicity also. Acetylcholinesterase inhibitor Antifungal

Oleacein Thirty-one analogs

Anti-inflammatory Larvicidal

[113] [114]

Four analogs

Cytotoxic

[115]

Uncaring acid C

Inhibitor of Ab42 aggregation Cytotoxic

[116]

Twelve analogs Fifteen analogs

Cytotoxic and antibacterial

[112] [60]

[117] [118]

Semisynthesis of Bioactive Compounds and their Biological Activities

Matrine (alkaloid)

Bioactivity of semisynthetic derivatives

12

Table 1.1 Developments in the biological activities of semisynthetic derivatives.dcont'd

Withanolide D (steroid)

Melia azedarach (Meliaceae) Malus domestica and Platanus acerifolia (Rosaceae and Platanaceae) Withania somnifera L. (Solanaceae)

Twelve analogs

Insecticidal

[119]

Twenty-four analogs

Antimalarial and cytotoxic

[120]

Twenty-five analogs

Cytotoxic

[121]

Preliminary concept of semisynthesis and its importance

Toosendanin (triterpenoid) Ursolic and betulinic acid (triterpenoid)

13

14

Semisynthesis of Bioactive Compounds and their Biological Activities

properties, by blending, crosslinking, or grafting [124]. Often, natural polymers are synthetically modified to change or enhance their properties [125]. Semisynthetic polymers, therefore, have the potential to overcome the limitations associated with only natural and only synthetic carriers [126]. In 2018, Seabra et al. reported nitric oxide (NO) nanoparticles/hydrogels that can be used as topical agents [127]. NO serves as a signaling compound in the skin. Dermal blood flow, tissue repair, and skin defense are all governed by it. Developing topical formulations that release NO/NO donors directly at the application site is becoming increasingly important. An NO donor S-nitrosoglutathione was incorporated into natural polycationic linear polysaccharide chitosan nanoparticles (hydrodynamic size of 112.2  2.22 nm). Pluronic F-127 hydrogels have been formulated with free S-nitrosoglutathione or S-nitrosoglutathione-bearing chitosan nanoparticles. Dermal evaluations have been conducted on murine models. Incorporating these systems has been shown to improve the physicochemical and biological properties of both polymers. A hydrophobic polyphenol, curcumin, is obtained from the rhizome of Curcuma longa, and an isoflavone known as genistein is present in unprocessed soybeans [128,129]; these are two phytotherapeutics that has been extensively studied for their potential to promote health and prevent disease, including cancer [130]. In order to improve the oral bioavailability of curcumin and genistein, Ko and his colleagues fabricated curcumin and/or genistein-encapsulated nanostructured lipid carriers. A co-loading of curcumin and genistein did not adversely affect their solubility and stability. A chemical modification of curcumin’s chemical structure improves its anticancer properties [131]. In this regard, pyrazole-curcumin analogs were most effective [132]. Valentine et al. synthesized a heteroleptic palladium II complex using curcumin and bipyridine. In hormone-independent prostate cancer cell lines, the analogue induces apoptosis and inhibits cell proliferation more efficiently than curcumin alone [133]. Thirteen curcumin analogs were synthesized, and the semisynthesized heterocyclic analogue of curcumin showed greater potency in a study by Fuchs and co-workers [134]. Using natural polymers such as chitosan, dextran, alginate, etc., as carriers for different drug categories, such as anticancer drugs, antibiotics, probiotics, etc., has been widely explored [135]. Developing nanoparticle drug delivery systems using natural and synthetic polymers is possible. In order to stabilize the nanoparticles derived from natural polymers, such as chitosan, alginate, etc., different chemical modifications have been applied to these polymers to

Preliminary concept of semisynthesis and its importance

15

enhance their ability to cross biological barriers [136,137]. Various chitosan derivatives were generated by utilizing the primary amino and hydroxyl groups in the glucosamine units of natural chitosan. As a result of these modifications, novel polymeric materials were developed with various biopharmaceutical and physicochemical properties, such as solubility, pH sensitivity, adsorption, and thermostability [138,139]. Chemical modifications of chitosan include thiolation, succinylation, carboxymethylation, grafting, and copolymerization. The amine groups of chitosan were coupled with carboxylic acids to form amidic linkages to the polymer’s backbone. When chitosan was grafted with carboxylate groups, its surface charge decreased, decreasing its cytotoxicity. The cationic surface of chitosan was responsible for the electrostatic complexation with phospholipids in the membrane, resulting in the rupture [140]. Numerous chitosan derivatives have been successfully used as nanocarriers for transporting vitamins, phytochemicals like catechin, probiotics including Lactobacillus acidophilus, and enzymes such as trypsin [141]. Zhang and co-workers reported using cellulose stearoyl esters as vehicles for the preparation of nanoparticles by nanoprecipitation and dialysis [142]. This study demonstrated that the size of the nanoparticles produced depends on the molecular weight of the cellulose and the temperature at which it is synthesized. The effectiveness of these chitosan derivatives as nanocarriers can also be influenced by factors like the droplet formation mechanism and the polymeric solution’s concentration. Several drugs, including nonsteroidal anti-inflammatory, anticancer, and antibacterial agents, have been delivered by cellulose or cellulose derivatives-based nanoparticles [143].

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CHAPTER TWO

Semisynthesis of antibiotics 2.1 Current antibiotic resistance mechanism Infections are the leading cause of death worldwide [1]. Infectious diseases pose a significant threat to humans. With the discovery of antibiotics, there was optimism that infections could be prevented and controlled. However, antimicrobial resistance is one of the most urgent challenges facing the globe. Bacterial infections caused one out of every eight deaths in 2019, the second most prevalent cause of death worldwide [2]. Antibiotic resistance occurs when bacteria change in response to the application of antibiotics; to prevent and treat bacterial infections, antibiotics are used as medicines. Today, drug-resistant infections are among the most pressing health concerns. In most cases, isolates of Staphylococcus aureus resist penicillin; penicillins are used to treat bacterial infections [3]. Gram-negative bacterial infections are well known. Many other bacterial pathogens have developed resistance to more antimicrobial agents, making it difficult to treat infections caused by them [4]. Glycopeptide antibiotics vancomycin (103) and teicoplanin (129) serve as the final resort when combating life-threatening infections instigated by Gram-positive human pathogens. These antibiotics are notably effective in treating staphylococcal infections, particularly those caused by methicillinresistant Staphylococcus aureus (MRSA) [5]. Their use, however, is limited by the emergence of glycopeptide resistance and acute side effects [6]. The word “antibiotic” obtains from the Greek “antibiotikus” (“anti” meaning against and “biotikus” meaning fit for life). Hence, antibiotic means “lifekilling”. The appearance of antibiotic resistance in pathogenic bacteria has become the main warning to worldwide public health. Understanding the mechanism behind antibiotic resistance is the first step in developing effective methods for addressing this issue. Three fundamental mechanisms underpin antimicrobial resistance: the enzyme degradation of b-lactam antibiotics, modifications in the proteins within bacteria that are likely targeted by antimicrobial agents, and changes in membrane, limiting antibiotic penetration [7]. Based on the mechanism of action, Table 2.1 represents the various antimicrobial groups [8e10]. Table 2.2 provides antimicrobial resistance mechanisms in Staphylococcus aureus [11]. Semisynthesis of Bioactive Compounds and their Biological Activities ISBN: 978-0-443-15269-6 https://doi.org/10.1016/B978-0-443-15269-6.00007-9

© 2024 Elsevier Inc. All rights reserved.

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j

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Semisynthesis of Bioactive Compounds and their Biological Activities

Table 2.1 A classification of antimicrobials based on their mode of action. Antimicrobial groups Mechanism of action

Tetracyclines Chloramphenicol Oxazolidinones Lincosamides Penicillins Cephalosporins b-Lactams Monobactams Fluoroquinolones Quinolones Lipopeptides Trimethoprim Sulfonamides Table 2.2 Types of Staphylococcus aureus. Antimicrobial agents

Chloramphenicol b-Lactams Tetracyclines Glycopeptides Fluoroquinolones Streptogramins Tetracyclines Lipopeptides Macrolides b-Lactams

Inhibit protein synthesis

Inhibit cell wall synthesis

Inhibit the nucleic acid synthesis Depolarize cell membrane Inhibit metabolic pathways

antimicrobial

resistance

mechanisms

of

Resistance mechanism

Drug inactivation

Limiting the intake of drugs Active drug efflux Modification of drug target

2.2 Chemical derivatization of antibiotics This section aims to deal with the chemical derivatization of antibiotics.

2.2.1 Semisynthesis of platencin thioether derivatives Pathogenic bacteria are becoming increasingly antibiotic-resistant, which seriously threatens public health worldwide. Antibiotics are used to prevent and treat bacterial infections, and antibiotic resistance occurs when bacteria change over time and are no longer responsive to drugs. A multitarget monotherapeutic antibiotic is applied in clinical settings to decrease antibiotic resistance development [12]. The semisynthesis of platencin thioether derivatives from Platencin, a natural antibiotic, was reported by Huang et al.

Semisynthesis of antibiotics

27

in 2021, along with a biological evaluation of these semisynthetic derivatives (Scheme 2.1) [13]. A potent inhibitor, platencin (1), was isolated from Streptomyces platensis MA7339 in Spain [14]. The tricyclic cage unit of platencin (1) is biosynthesised from an ent-atiserene precursor and a 3-amino-2,4dihydroxybenzoic acid moiety, both of which can interact with FabF (critical active-site residues Cys-His-His) and FabH (Cys-Asn-His). Platencin (1) was initially treated with H2O2 in the presence of catalytic amounts of tetrabutylammonium fluoride (TBAF) in DCM and LiOH (2 M) to yield platencin oxirane (2) as a single isomer with high regioselectivity at room temperature via oxidation reaction in 90% yield. The presence of a stereohindered cage structure in platencin (1) is thought to play a significant role in its high stereoselectivity and regioselectivity. This effect is likely attributed to the specific positioning of the double bonds, resulting in significantly enhanced reactivity at the C6eC7 position compared to the exo position (C15eC16) in platencin (1). In a green synthesis protocol, 14 platencin thioether analogs (3e16) were synthesised from 2 in ethanol:water (5:1) at room temperature via thiolysis using RSH and LiOH (2 M) with moderate to high yields (4694%) [15]. Several thioether analogs of platencin contain sulfur-containing substituents at C6 that are substituted with halogencontaining phenyl groups, heterocycles (pyridine, thiophene, pyrimidine, furan), and cyclohexane as well as hydrophilic aliphatic alcohols [13]. The antibacterial properties of the platencin derivatives (2L16) were also assessed. Semisynthetic derivatives 9, 11, 14, and 15 were found to possess antibacterial properties comparable to platencin (1) when tested in vitro against Staphylococcus aureus strains. Several platencin analogs, including 4, 6, 9, 11, 14, and 15, showed minimum inhibitory concentrations (MICs) of 1e2 mg/mL against various S. aureus strains [13].

Scheme 2.1 Semisynthesis of platencin thioether derivatives.

28

Semisynthesis of Bioactive Compounds and their Biological Activities

2.2.2 Semisynthesis of dialkylresorcinol derivatives Dialkylresorcinols are natural products derived from plants and bacteria, primarily Pseudomonas [16]. It has been shown that these compounds possess cytotoxic, antibacterial, antifungal properties [17,18] and additional potential benefits [19]. Clark et al. isolated two dialkylresorcinol compounds, 5-heptyl-2-hexylresorcinol (17) and 2-hexyl-5-pentylresorcinol (18), from the bacterium Pseudomonas aurantiaca YM03-Y3, and have prepared semisynthesised analogs of these two compounds [20]. Chemical derivatisation can be carried out at two notable positions in compounds, 17 and 18; two hydroxyl groups (-OH) directly attached to the aromatic ring and two aromatic hydrogen atoms (-H) located at positions 4 and 6 of activated resorcinol rings. In CCl4, succinimide reagents (NCS, NBS & NIS) were used to halogenate the aromatic hydrogen atoms of 5heptyl-2-hexylresorcinol (17) into mono- and di-halogenated products (19e24). In addition, resorcinol (17) in acetonitrile (ACN) was alkylated with alkyl halides in the presence of K2CO3 to give its ether derivatives (25e27) by alkylation of the phenolic hydroxyl groups (Scheme 2.2). Resorcinol (17) readily reacts with propargyl bromide, producing only the disubstituted product 25. Using acetyl chloride in ACN, resorcinol (17) was acetylated to give 28 in good yield (93%). Two fluorosulfate derivatives, 29 (19%) and 30 (71%), were obtained from resorcinol (17) by using sulfuryl fluoride as a catalyst. Additionally, several semisynthetic derivatives (31e39) were synthesised using 2-hexyl-5-pentylresorcinol (18) as a starting material (Scheme 2.3). It was found that semisynthetic derivatives, such as mono-halogenated compounds 19, 21, and 23, as well as methyl ether 26, retained their activity against the parent compound 17. In contrast, the mono-fluorosulfated compound 29 demonstrated an improved activity against all four tested strains. Regarding their activity, the mono-halogenated derivatives 31, 33, and 35 were comparable to the starting compound 18. The monofluorosulfated derivative 38, on the other hand, exhibited higher activity against S. aureus and S. epidermidis with MIC values of 1.1 and 2.1 mg mL1, respectively. Compared to 17, natural 2-hexyl-5pentylresorcinol (18) showed better antimicrobial activity [21] due to a shorter alkyl side chain.

Semisynthesis of antibiotics

29

Scheme 2.2 Semisynthesis of dialkylresorcinol derivatives.

Scheme 2.3 The chemical structures of semisynthetic derivatives of 2-hexyl-5pentylbenzene-1,3-diol (18).

2.2.3 Semisynthesis of unguinol derivatives By cultivating Aspergillus unguis on a large scale, it is possible to obtain depsidone unguinol (40), the organism’s main metabolite [22]. The semisynthesis of unguinol (40) derivatives by benzylation of the fungal depsidone antibiotic has been reported by Morshed and co-workers in recent years, in which preliminary SAR studies indicate that benzylation of the 3-OH group of unguinol (40) significantly increases its antibacterial activity, particularly against Staphylococcus aureus [23]. Ten second-generation 3-O-benzylated derivatives (41aej) were obtained by treating unguinol (40) with benzyl bromide at 50 C (Scheme 2.4). Three picolyl derivatives (41k-m) were obtained by combining depsidone unguinol (40) with 2-, 3-, and 4-picolyl chloride in acetonitrile at 25 C. In acetonitrile at 25 C, unguinol (40) is alkylated with 4-(2chloroethyl) morpholine, 1-(2-chloroethyl) pyrrolidine, and 1-(2chloroethyl) piperidine to produce compounds (41nep) by alkylation of the 3-OH group of 40. The synthesis of compounds (42a-c) has been accomplished by hydrogenation and benzylation of unguinol (40) using three benzyl bromides [23].

Scheme 2.4 Semisynthesis of unguinol derivatives.

Semisynthesis of antibiotics

31

2.2.4 Semisynthesis of arsinothricin In the 2019 EPA (Environmental Protection Agency) chart, arsenic ranks as the most prevalent toxic substance and carcinogen in the environment. Most organisms cannot survive life in an environment where arsenic is present. Some members of microbial communities, however, use arsenic as a weapon against other bacteria in a constant struggle for supremacy. In recent years, it has been discovered that the rice rhizosphere bacterium Burkholderia gladioli GSRB05 synthesises a novel arsenic-bearing compound known as arsinothricin (2-amino-4-(hydroxymethylarsinoyl)-butanoic acid (AST) (46) [24]. A broad-spectrum antibiotic, AST (46), is effective against both Gram-positive and Gram-negative bacteria, including Enterobacter cloacae (CRE) and Mycobacterium bovis BCG [25]. In 2020, Yoshinaga et al. developed a semisynthetic method of synthesising AST (46), which involved the enzymatic methylation of hydroxyarsinothricin (AST-OH (43)) [24]. In their study, it was observed that B. gladioli GSRB05 initially produces AST-OH (43) when exposed to trivalent inorganic arsenite; after that, it gradually biotransforms into the desired AST (46), suggesting that the final step of AST biosynthesis is the methylation of AST-OH (43) to AST (46) [26]. Therefore, the authors attempted a semisynthesis from AST-OH (43) in order to provide trivalent AS (III)T-OH (44) through a chemical reduction in the presence of Na2S2O3, Na2S2O5 and H2SO4 (Scheme 2.5). Then, compound 44 was converted to the trivalent form of AST (45) largely (>70%) in the presence of the robust thermostable enzyme CmArsM through the transfer of the S-methyl group, probably as a mixture of the D/L-enantiomers. Finally, As (III)T (45) spontaneously generated AST (46) by oxidation in the air.

Scheme 2.5 Semisynthesis of arsinothricin.

32

Semisynthesis of Bioactive Compounds and their Biological Activities

2.2.5 Semisynthesis of fidaxomicin derivatives Glycosylated macrocyclic lactone fidaxomicin (47, tiacumicin B) was produced from actinomycetes, and four different soil bacteria also produced this macrolide antibiotic (47) [27,28]. Fidaxomicin (47), an atypical antibiotic, exhibits good to excellent antibiotic activity against Gram-positive bacteria. It has been approved for treating Clostridium difficile infections with MIC values ranging from 0.012 to 0.25 mg/mL [29]. As a result of its low water solubility and poor systemic absorption, fidaxomicin (47) has not yet been proven effective in treating systemic infections. Developing semisynthetic derivatives is currently a promising strategy for improving water solubility. A one-step protection group-free preparative methodology (Scheme 2.6) was employed by Gademann et al. for the semisynthesis of novel fidaxomicin derivatives from the natural product fidaxomicin (47) [30]. To enhance the polarity and to take advantage of the common medicinal application of compounds (48e53), substituents were inserted into semisynthetic derivatives. Compounds (48L56) were derived as separable mixtures of mono- and disubstituted compounds other than 55b [31]. Intriguingly, monosubstitutions occurred predominantly at the 5000 -hydroxyl group due to the possibility that electronic effects would confer a higher nucleophilicity on this hydroxyl group. The same investigators also prepared hybrids of fidaxomicin (47) with other antibiotics. For the preparation of the fidaxomicin-ciprofloxacin hybrid 59a, ciprofloxacin (57) was initially converted into the corresponding bromoacetyl-ciprofloxacin 58 in the presence of the bromoacetyl bromide and compound 58 was reacted with fidaxomicin (47) in basic conditions (K2CO3 in DMF) to afford desired hybrid 59 (Scheme 2.7). The fidaxomicinrifampicin hybrid was also synthesized.

Semisynthesis of antibiotics

Scheme 2.6 Semisynthesis of fidaxomicin derivatives.

33

34

Semisynthesis of Bioactive Compounds and their Biological Activities

Scheme 2.7 Semisynthesis of fidaxomicin-ciprofloxacin hybrid.

2.2.6 Semisynthesis of amidochelocardin derivatives An atypical tetracycline amidochelocardin (60) originated through genetic engineering of the chelocardin producer strain [32]. Bronstrup et al. accomplished the semisynthetic modification of an antibiotic amidochelocardin or 2-carboxamido-2-deacetyl-chelocardin (60) involving methylation, acylation, oxidative CeC coupling reactions, and electrophilic substitution as key steps at C4, C7, C11, and C10 positions to afford amidochelocardin derivatives (61e67) (Scheme 2.8) [32].

Semisynthesis of antibiotics

35

Scheme 2.8 Semisynthesis of amidochelocardin derivatives.

2.2.7 Semisynthesis of nidulin derivatives Aspergillus unguis and Aspergillus nidulans are common fungi that produce nidulin (68), nornidulin (69), and other depsidones primarily through fermentation [33]. It was shown that nidulin (68) displayed activity against Gram-positive bacteria such as Bacillus cereus with a MIC value of 1.56 mg mL1 and Enterococcus faecium with a MIC value of 3.13 mg mL1. At the same time, nornidulin (69) exhibited weaker activity than that of nidulin (68) [34,35]. Based on the structure-activity relationship (SAR), it has been observed that the 3-OH group is essential to antibacterial activity. Isaka et al. considered nornidulin (69) as a substrate for the semisynthesis of 8-O-substituted derivatives predominantly; substrate 69 was derived from

36

Semisynthesis of Bioactive Compounds and their Biological Activities

the commercial strain A. unguis ATCC 10032 [34]. In a highly regioselective manner, nornidulin (69) was treated with alkyl, benzylic, or allylic halides (R-X; X ¼ I, Br, Cl, one equivalent), and K2CO3 (2 equiv) in DMF, at room temperature to obtain 8-O-substituted derivatives (70e84) (Scheme 2.9). The antibacterial activity of semisynthetic derivatives was evaluated, and several derivatives were found to have more powerful antibacterial properties than nidulin (68). Specifically, 8-O-arylether derivatives possess potent antibacterial properties against Gram-positive bacteria containing methicillin-resistant Staphylococcus aureus. Among these semisynthetic derivatives, compound 72 (8-O-butyl) demonstrated the greatest activity against B. cereus with a MIC value of 0.391 mg mL1.

Scheme 2.9 Semisynthesis of nidulin derivatives.

2.2.8 Semisynthesis of teicoplanin derivatives Teicoplanin is a class of glycopeptide antibiotics that are structurally related to vancomycin. Teicoplanin was discovered in 1978 in the fermentation broth of Actinoplanes teichomyceticus [36] in India. It prevented and treated serious infections caused by Gram-positive bacteria, including MRSA and enterococci. Due to its inability to cross the cell wall of Gram-negative bacteria, it is ineffective against them [37]. A study by Herczegh et al. presented the synthesis of new semisynthetic teicoplanin derivatives and evaluated their antibacterial activity in vitro [38]. Following their previously reported method, they synthesised by preparing the pseudoaglycon derivative 85 of teicoplanin (Scheme 2.10) [39]. In the presence of the 3-(dimethylamino)-1-propylamine and 3-(diethylamino)-1-propylamine and the peptide coupling reagent PyBOP, the respective two amide analogs 86 and 87 were synthesised from 85. A Cu(I)-catalyzed azidealkyne cycloaddition (CuAAC) was key in synthesising triazole derivatives 88 and 91 from the teicoplanin

Semisynthesis of antibiotics

37

complex. From triazole derivative 88, analogs 89 and 90 were synthesised similarly to those described earlier for analogs 86 and 87. Using the selected amines, amides 92 and 93 were prepared by peptide coupling with aglycon compound 91. Azido derivatives were generated by diazotransfer from the teicoplanin mixture. Then, CuAAC provided the triazole derivative 94, and the amide analog 95 was synthesised from 94 as reported for the other amide derivatives (Table 2.3).

Scheme 2.10 Semisynthesis of teicoplanin derivatives (85e95).

2.2.9 Semisynthesis of platensimycin derivatives Platensimycin (PTM) is an antibiotic produced by the soil bacterium Streptomyces platensis [40]. A major step was developed by Huang et al. to semisynthesize 20 platensimycin derivatives through Suzuki-Miyaura cross-coupling reactions, as platensimycin’s poor pharmacokinetics inhibit further clinical improvement [41]. Based on their previous study [42], platensic acid (PTMA) ethyl ester 97 was prepared from natural platensimycin (96) in 90% yield through hydrolysis. To develop a more effective protocol, approximately 33 mg of platensimycin (96), the flagship antibiotic of a new class of antibiotics, were obtained per gram of resin; the adsorbed platensimycin (96) was liberated with ethyl alcohol and hydrolyzed by H2SO4 to produce platensic acid (PTMA) ethyl ester 97. Interestingly, more than 10 g of starting material 97 can be obtained from 500 g of dried resins, sufficient for further structural modifications [41]. An iodine catalyst, DMAP (4-dimethylaminopyridine), was used in tetrachloromethane/pyridine at 90 C to obtain compound 98 from platensic acid ethyl ester 97 in 95% yield (Scheme 2.11). Then, in a 1:1 mixture of DME (glycol dimethyl ether) and water, an iodine intermediate 98 undergoes Suzuki-Miyaura cross-coupling to afford 99aLt in 85e95% yield using borophenylic acid, Na2CO3, and a catalytic amount of 10% Pd(0)/C. Stronger bases, such as KOH, NaOH, or organic base Et3N (triethylamine), yielded no products. Through hydrolysis

Table 2.3 Structures of the prepared teicoplanin analogs. Compound no. R1

R2

R3

H

86

H

H

(b-D-GlcNAc) b-D-GlcNAc

87

H

H

b-D-GlcNAc

88

H

89

H

(a-D-Man) a-D-Man

b-D-GlcNAc

90

H

a-D-Man

b-D-GlcNAc

91

H

H

H

92

H

H

H

93

H

H

H

a-D-Man

b-D-GlcNAc

a-D-Man

b-D-GlcNAc

94

95

(N-acyl-b-D-GlcN) R0 ¼ 8-methylnonanoyl, n-decanoyl N-acyl-b-D-GlcN

OH

b-D-GlcNAc

OH

OH

OH

Semisynthesis of Bioactive Compounds and their Biological Activities

H

38

85

R4

Semisynthesis of antibiotics

39

in the presence of 2 M LiOH in THF/water (1:1), the corresponding arylPTMAs were synthesised from compounds (99a-t). Coupling the newly synthesised PTMA derivatives with the 2-trimethylsilylethyl (TMSE) ester 100 in dry DMF (dimethylformamide) and Et3N, the TMSE-protected PTM derivative 101 was obtained. A catalytic amount of TBAF (tetrabutylammonium fluoride) in THF (tetrahydrofuran) was used to remove the TMSE-protecting group from compound 101, leading to compounds (102a-t) in 70e85% yield. 102s and 102t, two porensimycin analogs, were evaluated for antibacterial activity. Against MRSA in a mouse peritonitis model, 6-pyrenyl platensimycin (102t) exhibited better antibacterial activity than parent platensimycin (96). Compared with platensimycin, compound 102t possesses a MIC (minimum inhibitory concentration) of only 4 mg/mL when tested with 10% human serum.

Scheme 2.11 Semisynthesis of platensimycin derivatives.

2.2.10 Semisynthesis of glycopeptides The glycopeptide antibiotic vancomycin (103) was isolated in 1956 from Streptomyces orientalis [43]. Through the amidation of natural antibiotics, Olsufyeva et al. synthesised novel glycopeptides 105e108 from vancomycin (103) or eremomycin (104) in 2018 (Scheme 2.12) [44]. By using PyBOP

40

Semisynthesis of Bioactive Compounds and their Biological Activities

(benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) as a coupling reagent in dimethyl sulfoxide, vancomycin (103) or eremomycin (104) was reacted with pyrrolidine or piperidine hydrochloride in the presence of Et3N (pHw8.5) to obtain pyrrolidides or piperidides of vancomycin 105 and 106 or eremomycin 107 and 108 in 48e66% yields.

Scheme 2.12 Semisynthesis of glycopeptides.

2.2.11 Semisynthesis of lipopeptides The development of novel antibiotics is motivated by the unique structure of the polycyclic antibacterial peptide nisin, which contains 34 amino acid residues and exhibits potent activity. Nisin (109), however, has certain limitations due to its peptidic structure (Fig. 2.1). In particular, its disadvantages

Semisynthesis of antibiotics

41

Fig. 2.1 Structure of nisin, the preeminent lantibiotic.

include its susceptibility to proteolytic degradation in vivo, poor pharmacokinetics, and toxicity [45]. Several chemical strategies have also been employed to achieve desirable properties in synthesising lantibiotics [46] and their analogs [47,48]. Due to the complex structure of nisin (109), the total synthesis presents greater challenges. An alternative approach to synthesising lantibiotics with desirable properties is a semisynthesis in which a naturally occurring compound is synthetically modified. Using natural bacteriocin nisin (109), Martin et al. developed semisynthetic lipopeptides that were both antibacterially active and proteolytically stable (Scheme 2.13) [49]. An antimicrobial agent, lantibiotic nisin (109), was first identified in 1928 in fermented milk cultures [50]. It was produced from several strains of Lactococcus lactis and commercially marketed in England in 1953 [51]. In order to generate semisynthetic lapidated constructs 111e116 from compound 110, the lipid amine was coupled with the C-terminus of the nisin A/B ring system using BOP/DIPEA for a short period. These constructs have potent antibacterial activity. The most attractive activity was found against clinically relevant bacterial strains such as MRSA and VRE. Notably, anti-VRE activity was comparable to the natural peptide nisin (109) with enhanced stability. In order to obtain compound 117, compound 110 alone was treated with BOP/DIPEA. Through the click reaction, compound 116 was ligated with an equivalent of an alkyne-modified lipid under microwave irradiation in the presence of a ligand TBTA to obtain compounds (118e123) (Scheme 2.14).

Scheme 2.13 Semisynthesis of lipidated analogs.

Scheme 2.14 Semisynthesis of triazole-coupled analogs.

Semisynthesis of antibiotics

43

2.2.12 Semisynthesis of caprazene derivatives By adding several amines, alcohols, and anilines to the carboxyl function of the diazepinone ring, Akamatsu et al. synthesised new semisynthetic antibiotics from caprazamycins A-G [52]. Caprazamycins were first isolated from Streptomyces sp. MK73062F2 in 2003 [53]. A liponucleoside antibiotic caprazamycin is structurally composed of 1,4-diazepanone, a seven-membered ring containing two nitrogen atoms, a uridine 3-methylglutaric acid moiety, and a fatty acid moiety. Based on the difference in the fatty acid content of capsamycins (CPZs), they are divided into seven classes (AeG) [52]. The main component of caprazamycins is caprazamycin B (CPZ-B), which showed potent antimycobacterial activity and was viewed as a promising anti-TB drug candidate [54]. However, certain limitations prevent its development as a new anti-TB drug, including a poor water-solubility profile and difficulty isolating it from complex mixtures using HPLC. In order to overcome the disadvantages of CPZ-B, investigators studied the derivatisation of caprazene (CPZEN, 124), which is the core structural component of CPZs; quantitatively, CPZEN (124) can be derived from CPZ-B [55]. CPZEN comprises a 5-amino-D-ribose moiety, a uridine moiety, and a diazepinone ring. It is advantageous because it lacks a fatty acid moiety that would cause a complex mixture to be formed. To obtain the triethylamine salt of the N-Boc derivative 125, CPZEN was reacted with Boc2O and triethylamine. As a result of the condensation of carboxyl groups of 125 with various amines or anilines, the protective group (Boc) was removed from the primary amino group, yielding alkylamides 126aes and anilides 127aeh (Scheme 2.15). Additionally, the ester derivatives (128aee) were synthesised by condensation of 125 with different alcohols, followed by deprotection of the N-Boc group. Derivatisations were carried out using the carboxyl group adjacent to the fatty acid-binding site and enhancing water solubility by constructing acid salts of the basic molecules to preserve a free amino group. Caprazene did not exhibit any antibacterial activity. In contrast to CPZ-B, many CPZEN derivatives showed excellent antibacterial activity against mycobacteria. Comparatively to CPZ-B, compounds 127b (CPZEN-45), 127d (CPZEN-48), and 127g (CPZEN-51) showed greater activity against Mycobacterium tuberculosis and M. avium complex strains.

44

Semisynthesis of Bioactive Compounds and their Biological Activities

Scheme 2.15 Semisynthesis of caprazene derivatives.

2.3 Recent advances in the clinical applications of antibiotics and their analogs A major threat to world health is the emergence of multi-drug-resistant (MDR) bacteria. Global health is also at risk due to reducing the

Semisynthesis of antibiotics

45

invention of new antibiotics. In 2019, antimicrobial resistance (AMR) contributed to the deaths of 1.27 million people [56]. AMR was also estimated to be responsible for 4.95 million deaths. Moreover, 0.5 million deaths were attributed to methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae alone in 2019 [56]. Glycopeptides are the most significant anti-Gram-positive agents. Due to antibiotic resistance, we need new analogs with improved properties and safety profiles [57]. Semisynthesis is the most practical method for accessing new analogs in quantities appropriate for clinical development [58]. In 1952, vancomycin (103) was discovered based on a soil sample containing Streptomyces orientalis, the microorganism responsible for generating vancomycin (103) [59]. Obtaining its name from the word “vanquish,” vancomycin (103) possesses potent antibacterial properties against different Gram-positive strains containing penicillin-resistant Staphylococcus aureus [59]. After successful clinical trials, the glycopeptide antibiotic vancomycin (103) was finally isolated. Vancomycin (103) is currently used as the firstline treatment for a variety of Gram-positive infections, including S. pneumoniae (MIC ¼ 0.06e2 mg/mL), MRSA (MIC ¼ 0.5e2 mg/mL), and Clostridioides difficile (MIC ¼ 0.125e4 mg/mL) [60]. Vancomycin (103) exhibits antibacterial properties due to its ability to firmly bind the lipid II precursor of bacterial cell walls and, consequently, inhibit cell wall synthesis [61]. Taking vancomycin (103) orally can alleviate C. difficilerelated diseases. As a relatively low protein binding compound (80%) [63]. Several instances of vancomycin have been used to treat bacterial infections (103), but its application has been associated with adverse effects, mainly nephrotoxicity and “Red Man Syndrome”. Due to the extensive use of 103 in clinics and avoparcin in veterinary practice, glycopeptideresistant strains have been developed [64]. New antibacterial antibiotics that are effective against poly-resistant bacteria, such as glycopeptideresistant strains, while reducing side effects remain challenging. Through the condensation of pyrrolidine or piperidine with vancomycin (103) or eremomycin (104) into glycopeptides 105e108, Olsufyeva et al. evaluated the antibacterial activity of new semisynthetic derivatives [44]. Compared to natural glycopeptide vancomycin (103) when diluted by 2e4 times, eremomycin pyrrolidide (107) demonstrates significantly greater potency and stands out as one of the most potent semisynthetic derivatives against S. aureus, Enterococcus strains, and coagulase-negative Staphylococcus. An MIC90 value of 1e2 mg/L was reported for vancomycin (103), while a

46

Semisynthesis of Bioactive Compounds and their Biological Activities

Fig. 2.2 Structures of the main components of teicoplanin (129).

value of 0.5 mg/L was reported for eremomycin pyrrolidide (107) for the genera Staphylococcus and Enterococcus (except E. faecium). Glycopeptide vancomycin (103) eventually led to the development of lipoglycopeptide teicoplanin (129) as the only other natural antibiotic to be used in clinical trials (Fig. 2.2). Nearly 30 years after vancomycin (103), the antibiotic teicoplanin (129) was discovered from Actinoplanes teichomyceticus. As a mixture of five linked lipids, the teicoplanin fatty acid motif produces teicoplanin A2-1 through A2-5, whose ratio can be controlled somewhat by fermentation conditions [65]. As a mixture of these five related compounds, glycopeptide teicoplanin (129) exhibits potent antibacterial activity against Gram-positive strains containing S. pneumoniae (MIC ¼ 0.06e0.25 mg/ mL), MRSA (MIC ¼ 0.25e2 mg/mL), and, notably, VanB-type VRE (MIC ¼ 0.25e8 mg/mL) [66]. In Europe, téicoplanin (129) is approved for intravenous and intramuscular administration in cases of Gram-positive infections. Studies have demonstrated that the carbohydrate residues in teicoplanin derivatives affect pharmacokinetics. The presence of N-acylglucosamine on amino acid four is particularly beneficial [67]. In response to the demand for new antibacterial drugs containing glycopeptide antibiotics, semisynthetic

47

Semisynthesis of antibiotics

Fig. 2.3 Structure of oritavancin (130).

derivatives have been developed with higher pharmacokinetic profiles against resistant pathogens. In 2019, Sz} ucs et al. synthesised different analogs (85e95) of teicoplanin pseudoaglycon derivatives involving systematic structural modifications [38]. New derivatives of teicoplanin (129) were evaluated in vitro with improved activity against VanA-type vancomycinresistant enterococci (VRE). Regarding MIC values, the most active compound 87 (containing only acetyl-D-glucosamine as a carbohydrate moiety) is comparable to, or even lower than, the glycopeptide antibiotic oritavancin (130) against the tested strains of VRE (Fig. 2.3). Among the antibacterial agents employed in this study, vancomycin (103), teicoplanin (129), and oritavancin (130) were used as reference antibiotics. Several semisynthetic glycopeptide antibiotics, such as oritavancin (130), telavancin (131) (Fig. 2.4), and dalbavancin (132) (Fig. 2.5), have been approved for clinical use [68,69]. Oritavancin (130) is a semisynthetic glycopeptide antibiotic derived from the natural complex glycopeptide antibiotic chloroeremomycin isolated from Amycolatopsis orientalis [70]. This semisynthetic oritavancin (130) was obtained by combining a 40 -chlorobiphenylmethyl group with a disaccharide moiety. Oritavancin (130) exhibited potent antibacterial activity against both vancomycin-sensitive (MIC 0.008e0.25 mg/mL) and -resistant enterococci (MIC VanA 0.008e1, VanB 0.008e0.03) along with MRSA (MIC 0.008e0.5) [71,72]. Telavancin (131) is a semisynthetic glycopeptide antibiotic derived from vancomycin (103). Its structure differs from parent vancomycin (103) due to the decylaminoethyl modification on the vancosamine unit, which provides

48

Semisynthesis of Bioactive Compounds and their Biological Activities

Fig. 2.4 Structure of telavancin (131).

Fig. 2.5 Structure of dalbavancin (132).

greater activity against Gram-positive bacteria [73]. In contrast to teicoplanin (129), telavancin (131) is highly effective against VISA strains [74]. Furthermore, it exhibits activity against several Gram-positive species, including VanB-type VRE (MIC ¼ 2 mg/mL), MRSA (MIC ¼ 0.016e0.125 mg/ mL), and S. pneumoniae (MIC ¼ 0.008e0.03 mg/mL) [75]. This antibiotic, dalbavancin (132), was prepared from A40926, a glycopeptide antibiotic

Semisynthesis of antibiotics

49

produced by an actinomycete with anti-Neisseria activity [76]. 3-(Dimethylamino)-1-propylamine provides an amidation of the C-terminus during the three-step synthesis [77]. The drug dalbavancin (132) was used to treat acute bacterial skin and skin structure infections (ABSSSI) caused by Grampositive bacteria [78]. In addition, it demonstrated potent antibacterial activity against Gram-positive strains such as streptococci (MIC 0.03 mg/mL), MRSA (MIC ¼ 0.06e1 mg/mL), and VanB-type VRE (MIC 0.03e4 mg/mL) [79]. In a C-terminal peripheral modification, Okano et al. inserted a quaternary ammonium salt, resulting in a binding pocket-modified vancomycin (103) analog, which employs a different mechanism of action than D-AlaD-Ala/D-Ala-D-Lac binding [80]. As a result of this modification, the antimicrobial activity of the drug is enhanced (200-fold) against vancomycin-resistant enterococci (VRE). It has also been observed that this type of C-terminal modification may be amalgamated by introducing a second peripheral (4-chlorobiphenyl)methyl (CBP) unit to the vancomycin disaccharide. As a result, more antimicrobial agents are available with a lower VRE MIC (minimum inhibitory concentration) of 0.01e0.005 mg/mL. In 2021, Lin et al. synthesised structurally new polyether ionophores by recycling components from extremely abundant polyethers through diversity-focused semisynthesis [81]. The obtained analogs exhibit enhanced antibacterial selectivity compared to a panel of naturally occurring polyether ionophores. A classic degradation reaction degraded the natural polyether antibiotic lasalocid and the first carboxylic polyether ionophore monensin. As a result of minute structural differences, antibacterial selectivity can be lost (HL342, reduction in carbonyl functionality compared to HL201, selectivity ratio 0.9 vs. 5.7). Recently, Herczegh et al. synthesised the first dimeric derivatives of antibiotic teicoplanin derivatives [82]. Using teicoplanin (129) as the starting material, they prepared four covalent dimers in two orientations in the presence of an a,u-bis-isothiocyanate linker. This study examines the relationship between teicoplanin (129) dimerisation and antibacterial activity. The pseudo-aglycon N,N- terminal homodimers of teicoplanin had a reduced potency against MRSA (MIC ¼ 4 mg/mL) than that of antibiotic teicoplanin (129) (MIC ¼ 0.5 mg/mL). Comparatively, homodimers were more effective against a VanA-type VRE strain with MICs of 4e8 mg/mL compared to teicoplanin (129) (MIC ¼ 256 mg/mL) [82]. The natural polycyclic antibacterial peptide nisin (109) has been semisynthesised by Martin et al. [49]. Generally, nisin A/B fragments do not

50

Semisynthesis of Bioactive Compounds and their Biological Activities

demonstrate antibacterial activity. Despite this, it has been synthetically modified to produce antibacterial as well as proteolytically stable derivatives. Among the synthesised analogs, compounds 113, 114, 115, and 121 display the strongest antibacterial activity against drug-susceptible and drug-resistant strains of Gram-positive bacteria. A unique lipid II-mediated mode of action and superior stability to nisin make semisynthetic lipopeptides promising candidates for further development as new antibiotics [49].

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[18] P. Anton, L. Jolanta, B. Anders, Antimicrobial dialkylresorcinols from Pseudomonas sp. Ki19, J. Nat. Prod. 69 (2006) 654e657. [19] S. Kato, K. Shindo, H. Kawai, M. Matsuoka, J. Mochizuki, Studies on free radical scavenging substances from microorganisms, J. Antibiot. 46 (1993) 1024e1026. [20] J. Li, Y. Shi, B.R. Clark, Semi-synthesis of antibacterial dialkylresorcinol derivatives, J. Antibiot. 74 (2021) 70e75. [21] E.C. Barnes, R. Kumara, R.A. Davis, The use of isolated natural products as scaffolds for the generation of chemically diverse screening libraries for drug discovery, Nat. Prod. Rep. 3 (2016) 372e381. [22] J.M. Kurung, Aspergillus ustus, Science 102 (1945) 11e12. [23] M.T. Morshed, H.T. Nguyen, D. Vuong, A. Crombie, E. Lacey, A.D. Ogunniyi, S.W. Page, et al., Semisynthesis and biological evaluation of a focused library of unguinol derivatives as next-generation antibiotics, Org. Biomol. Chem. 19 (2021) 1022. [24] S.H. Suzol, A.H. Howlader, A.E. Galvan, M. Radhakrishnan, S.F. Wnuk, B.P. Rosen, M. Yoshinaga, Semisynthesis of the organoarsenical antibiotic arsinothricin, J. Nat. Prod. 83 (2020) 2809e2813. [25] V.S. Nadar, J. Chen, D.S. Dheeman, A.E. Galvan, K.S. Yoshinaga, P. Kandavelu, B. Sankaran, M. Kuramata, S. Ishikawa, B.P. Rosen, M. Yoshinaga, Arsinothricin, an arsenic-containing non-proteinogenic amino acid analog of glutamate, is a broadspectrum antibiotic, Commun. Biol. 2 (2019) 131. [26] M. Kuramata, F. Sakakibara, R. Kataoka, K. Yamazaki, K. Baba, M. Ishizaka, S. Hiradate, T. Kamo, S. Ishikawa, Arsinothricin, a novel organoarsenic species produced by a rice rhizosphere bacterium, Environ. Chem. 13 (2016) 723e731. [27] F. Parenti, H. Pagani, G. Beretta, Lipiarmycin, A new antibiotic from Actinoplanes I. Description of the producer strain and fermentation studies, J. Antibiot. 28 (1975) 247e252. [28] M. Kurabachew, S.H.J. Lu, P. Krastel, E.K. Schmitt, B.L. Suresh, A. Goh, J.E. Knox, et al., Sambandamurthy, lipiarmycin targets RNA polymerase and has good activity against multidrug-resistant strains of Mycobacterium tuberculosis, J. Antimicrob. Chemother. 62 (2008) 713e719. [29] F. Babakhani, A. Gomez, N. Robert, P. Sears, Killing kinetics of fidaxomicin and its major metabolite, OP-1118, against clostridium difficile, J. Med. Microbiol. 60 (2011) 1213e1217. [30] A. Dorst, R. Berg, C.G.W. Gertzen, D. Sch€afle, K. Zerbe, M. Gwerder, S.D. Schnell, P. Sander, H. Gohlke, K. Gademann, Semisynthetic analogs of the antibiotic fidaxomicin-design, synthesis, and biological evaluation, ACS Med. Chem. Lett. 11 (2020) 2414e2420. [31] S.D. Schnell, L.V. Hoff, A. Panchagnula, M.H.H. Wurzenberger, T.M. Klapötke, S. Sieber, A. Linden, et al., 3-Bromotetrazine: labelling of macromolecules via monosubstituted bifunctional s-tetrazines, Chem. Sci. 11 (2020) 3042e3047. [32] C. Grandclaudon, N.V.S. Birudukota, W.A.M. Elgaher, R.P. Jumde, S. Yahiaoui, N. Arisetti, F. Hennessen, et al., Semisynthesis and biological evaluation of amidochelocardin derivatives as broad-spectrum antibiotics, Eur. J. Med. Chem. 188 (2020) 112005. [33] S. Sureram, S. Wiyakrutta, N. Ngamrojanavanich, C. Mahidol, S. Ruchirawat, P. Kittakoop, Depsidones, aromatase inhibitors and radical scavenging agents from the marine-derived fungus Aspergillus unguis CRI282-03, Planta Med. 78 (2012) 582e588. [34] M. Isaka, A. Yangchum, S. Supothina, S. Veeranondha, S. Komwijit, S. Phongpaichit, Semisynthesis and antibacterial activities of nidulin derivatives, J. Antibiot. 72 (2019) 181e184.

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[51] J. Delves-Broughton, P. Blackburn, R.J. Evans, J. Hugenholtz, Applications of the bacteriocin, nisin, Antonie Leeuwenhoek 69 (1996) 193e202. [52] Y. Takahashi, M. Igarashi, T. Miyake, H. Soutome, K. Ishikawa, Y. Komatsuki, Y. Koyama, et al., Novel semisynthetic antibiotics from caprazamycins AeG: caprazene derivatives and their antibacterial activity, J. Antibiot. 66 (2013) 171e178. [53] H. Nakamura, C. Tsukano, T. Yoshida, M. Yasui, S. Yokouchi, Y. Kobayashi, M. Igarashi, Y. Takemoto, Total synthesis of caprazamycin A: practical and scalable synthesis of syn-b-hydroxyamino acids and introduction of a fatty acid side chain to 1,4-diazepanone, J. Am. Chem. Soc. 141 (2019) 8527e8540. [54] M. Igarashi, N. Nakagawa, N. Doi, S. Hattori, H. Naganawa, M. Hamada, Caprazamycin B, a novel anti-tuberculosis antibiotic, from Streptomyces sp, J. Antibiot. 56 (2003) 580e583. [55] M. Igarashi, Y. Takahashi, T. Shitara, H. Nakamura, H. Naganawa, T. Miyake, Y. Akamatsu, Caprazamycins, novel lipo-nucleoside antibiotics, from Streptomyces sp. II. Structure elucidation of caprazamycins, J. Antibiot. 58 (2005) 327e337. [56] C.J.L. Murray, K.S. Ikuta, F. Sharara, L. Swetschinski, G. Robles Aguilar, A. Gray, C. Han, et al., Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis, Lancet 399 (2022) 629e655. [57] E. van Groesen, P. Innocenti, N.I. Martin, Recent advances in the development of semisynthetic glycopeptide antibiotics: 20142022, ACS Infect. Dis. 8 (2022) 1381e1407. [58] S. Majhi, D. Das, Chemical derivatization of natural products: semisynthesis and pharmacological aspects e a decade update, Tetrahedron 78 (2021) 131801. [59] R.S. Griffith, Vancomycin use e an historical review, J. Antimicrob. Chemother. 14 (Suppl. D) (1984) 1e5. [60] D.P. Levine, Vancomycin: a history, Clin. Infect. Dis. 42 (Suppl. 1) (2006) S5eS12. [61] M.A.T. Blaskovich, K.A. Hansford, M.S. Butler, Z. Jia, A.E. Mark, M.A. Cooper, Developments in glycopeptide antibiotics, ACS Infect. Dis. 4 (2018) 715e735. [62] B.H. Ackerman, E.H. Taylor, K.M. Olsen, W. Abdel-Malak, A.A. Pappas, Vancomycin serum protein binding determination by ultrafiltration, Drug Intell. Clin. Pharm. 22 (4) (1988) 300e303. [63] G.R. Matzke, G.G. Zhanel, D.R.P. Guay, Clinical pharmacokinetics of vancomycin, Clin. Pharmacokinet. 11 (1986) 257e282. [64] F.M. Aarestrup, A.M. Seyfarth, H.D. Emborg, K. Pedersen, R.S. Hendriksen, F. Bager, Effect of abolishment of the use of antimicrobial agents for growth promotion on occurrence of antimicrobial resistance in fecal enterococci from food animals in Denmark, Antimicrob. Agents Chemother. 45 (2001) 2054e2059. [65] A. Borghi, D. Edwards, L.F. Zerilli, G.C. Lancini, Factors affecting the normal and branched-chain acyl moieties of teicoplanin components produced by Actinoplanes teichomyceticus, Microbiology 137 (1991) 587e592. [66] A.L. Baltch, R.P. Smith, W.J. Ritz, L.H. Bopp, Comparison of inhibitory and bactericidal activities and postantibiotic effects of LY333328 and ampicillin used singly and in combination against vancomycin-resistant Enterococcus faecium, Antimicrob. Agents Chemother. 42 (1998) 2564e2568. [67] A. Malabarba, R. Ciabatti, R. Scotti, B. Goldstein, Octapeptide derivatives of teicoplanin antibiotics, J. Antibiot. 46 (1993) 661e667. [68] M.S. Butler, K.A. Hansford, M.A.T. Blaskovich, R. Halai, M.A. Cooper, Glycopeptide antibiotics: back to the future, J. Antibiot. 67 (2014) 631e644. [69] G.G. Zhanel, S. Trapp, A.S. Gin, M. DeCorby, P.R.S. Lagace-Wiens, E. Rubinstein, D.J. Hoban, J.A. Karlowsky, Dalbavancin and telavancin: novel lipoglycopeptides for the treatment of gram-positive infections, Expert Rev. Anti Infect. Ther. 6 (2008) 67e81.

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CHAPTER THREE

Semisynthesis of alkaloids 3.1 Function of plant alkaloids on human health Natural products and their structural analogs have played an important role in the discovery and development of drugs, improving our health, enhancing crop production, resolving complex ecological interactions, and constructing our way of life [1]. Various bioactive molecules are synthesized by plants, some of which can exhibit biodynamic properties suitable for both human and animal health [2e10]. One of the largest and most important groups of natural products is alkaloids, which plants primarily produce. Alkaloids contain nearly 20,000 compounds distributed throughout over 20% of the world’s known vascular plants. [11]; they are found in higher plants that belong to different families, such as Papaveraceae, Leguminosae, Apocynaceae, Ranunculaceae, Menispermaceae, and Loganiaceae, etc. [12]. Secondary metabolites are extremely diverse in terms of structure as well as biosynthetic pathways [13]. The origin of alkaloids can also be traced to microorganisms, marine organisms such as dinoflagellates, algae, and puffer fish, as well as terrestrial organisms such as salamanders, insects, and toads [14]. Chemically, alkaloids are nitrogencontaining molecules that may normally contain one or more nitrogen atoms in the heterocyclic ring. They are typically basic due to their heterocyclic tertiary nitrogen content [15]. Most alkaloids (alkali-like compounds) can react with acids to produce salts, indicating that they possess a basic character; notable exceptions include caffeine, colchicine, and paclitaxel. Since there is no clear borderline between alkaloids and naturally occurring complex amines, the specific meaning of the term ‘alkaloid’ is somewhat ambiguous [16]. Following Pelletier’s definition, an alkaloid is “a cyclic organic compound containing nitrogen in a negative oxidation state which is widely distributed among living organisms” [17,18]. Alkaloids are linked to many biological activities and hold substantial pharmaceutical potential; these compounds may find applications in lifesaving medications, veterinary medicine, toxicology, plant protection, and Semisynthesis of Bioactive Compounds and their Biological Activities ISBN: 978-0-443-15269-6 https://doi.org/10.1016/B978-0-443-15269-6.00008-0

© 2024 Elsevier Inc. All rights reserved.

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various other fields [15]. Among alkaloids, there are neuroactive substances such as nicotine and caffeine, antidotes such as emetine and cephaeline, which are employed to counteract oral intoxication, and antitumor agents like vincristine and vinblastine [11]. As a result of the toxicity of many alkaloids, they can act as defense molecules in plants, protecting them against pathogens and predators [14]. Plants can be used to manufacture many important drugs, including morphine, which is used for treating acute pain; quinine, which is employed because of its antimalarial properties and bitter taste; caffeine, which acts as a stimulant; serpentine and ajmalicine, which have antihypertensive properties; berberine and sanguinarine, which possess antimicrobial properties [11,16]. Since secondary metabolites and their structural analogs have historically played a crucial role in pharmacotherapy, particularly in treating cancer and infectious diseases, this section outlines the anticancer and antimicrobial activities of plant alkaloids.

3.1.1 Anticancer activity of plant alkaloids Cancer remains one of the leading causes of death worldwide due to its complexity and multifactorial nature. Over the last few decades, it has become evident that cancer cells can become resistant to traditional anticancer drugs, especially those in advanced stages, resulting in tumor relapses [19]. Therefore, an uninterrupted demand exists for developing new, more effective anticancer drugs and strategies [20]. In recent decades, secondary metabolites, particularly those derived from plants including alkaloids, have been a significant source of new drugs [3e10,21]. A significant role is played by plant-based drugs in the treatment of cancer at present [22]. As a result, this section discusses plant-derived alkaloids with potential anticancer activities (Table 3.1) since several plant-derived alkaloids have shown antiproliferative and anticancer properties in vivo and in vitro against various cancers [23,24].

3.1.2 Antimicrobial activity of plant alkaloids A significant increase in microbial resistance to traditional antibiotics has raised serious concerns about curing infectious diseases that threaten the community’s health [63]. In order to overcome the resistance of antibiotics, several studies and strategies have been proposed. Many phytochemicals including alkaloids have demonstrated significant antimicrobial properties against sensitive and resistant pathogens [64]. The investigation of novel antimicrobial agents derived from medicinal plants has received considerable attention in recent years [65]. The antimicrobial activity of plant alkaloids is shown in Table 3.2.

Fangchinoline (isoquinoline Stephania tetrandra alkaloid) Liriodenine (isoquinoline Enicosanthellum alkaloid) pulchrum Neferine (isoquinoline Nelumbo nucifera alkaloid)

Family

IC50/ED50

Cell lines

References

Menispermaceae

5 mM

[25]

Annonaceae

37.3 mM

Nelumbonaceae

10 mM

Bladder cancer cell lines T24 and 5637 Human ovarian cancer cell line CAOV-3 hTERT-immortalized retinal pigment epithelial cell line, human embryonic kidney 293 cells (HEK-293), and HeLa cells HEK-293 and human renal cancer SW839 cells Colorectal adenocarcinoma cell line DLD-1, immortal cell line HeLa, B16, U937, L1210, NIH-3T3, MHCC97-L, HepG2

Chelerythrine chloride (isoquinoline alkaloid)

Zanthoxylum simulans

Rutaceae

10 mM >40 mM

Berberine (isoquinoline alkaloid)

Ceriops decandra

Rhizophoraceae

1 mM 200 mM. Furthermore, this work demonstrated that the biaryl ether core is flexible and may be useful for the design of biologically potent natural product-based antiparasitic agents.

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Scheme 14.5 Semisynthesis of dehydrodieugenol B, methyl dehydrodieugenol B and synthetic analogs.

14.2.6 Semisynthesis of hederagenin methyl ester analogs Over 90 countries are affected by leishmaniasis, a neglected tropical disease caused by parasites of the trypanosome genus Leishmania [43,44]. The antileishmanial properties of semisynthetic saponins, a naturally occurring surface-active glycoside found in particular abundance in plants, were examined by Denny et al. in 2020 [45]. The triterpenoid sapogenin hederagenin

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Semisynthesis of Bioactive Compounds and their Biological Activities

was isolated from Hedera helix (common ivy) in a large amount which was transformed into a wide range of derivatives through chemical modification. During the investigation of a library of natural and semisynthetic saponins, hederagenin methyl ester (67) was transformed into a series of 2,23-O-acetal derivatives, including 69, which was obtained through the ester hydrolysis of 68 (Scheme 14.6). The semisynthetic compounds were screened with a phenotypic screening approach to identify effective and selective antileishmanial hits. Consequently, the investigation led to the identification of 12 compounds, among them the naturally existing saponin gypsogenin, which exhibited significant potency (ED50 < 10.5 mM) against axenic Leishmania mexicana amastigotes, the pathogenic form affecting mammals [45].

Scheme 14.6 Semisynthesis of hederagenin methyl ester analogs.

14.2.7 Semisynthesis of thiazinoquinone analogue thiazoavarone Using a natural sesquiterpene avarone (70), Menna and coworkers synthesized thiazoavarone (71) as a semisynthetic analogue of thiazinoquinone in 2020 for exploring the antileishmanial effects of the thiazinoquinone core (Scheme 14.7) [46]. As a result of the phytochemical analysis of Dysidea avara, the quinone avarone (70) and its reduced form avarol were identified following previously reported procedures [47]. In order to prepare thiazoavarone (71), an appropriate amount of avarone (70) was dissolved in a solution of CH3CN/C2H5OH (1:1), followed by hypotaurine and a catalytic amount of salcomine being mixed. During 48 h of stirring at room temperature (RT), pure thiazoavarone (71) was obtained. Avarone (70), avarol, and a novel semisynthetic thiazoavarone (71) were investigated for their antiparasitic activity against promastigotes and amastigotes of Leishmania infantum and Leishmania tropica. Further, density functional theory (DFT) was used to investigate the conformational and redox properties of natural metabolites

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and semisynthetic thiazoavarone (71). It has been also evident that antiparasitic activity is linked to the construction of a toxic semiquinone radical species [46].

Scheme 14.7 Semisynthesis of thiazinoquinone analogue.

14.2.8 Semisynthesis of dehydrodieugenol B and methyldehydrodieugenol B derivatives The Chagas disease is a tropical parasitic disease named after the Brazilian physician Carlos Chagas, who invented the disease in 1909 and has affected more than eight million people in developing countries [48]. As a result of the urgent need for biologically potent lead compounds for drug development against Chagas disease, Tempoone et al. conducted semisynthetic derivatizations of natural neolignans dehydrodieugenol B (44) and methyl dehydrodieugenol B (41) to examine how structural modifications affected their biological properties. In this study, 23 semisynthetic neolignan derivatives were prepared from natural compounds dehydrodieugenol B (44) and methyl dehydrodieugenol B (41) and their antiparasitic and cytotoxic activities against Trypanosoma cruzi were assessed. Five of these derivatives were active against trypomastigotes with IC50 values from 8 to 64 mM. In comparison, eight compounds were active against intracellular amastigotes with IC50 values between 7 and 16 mM and 18 derivatives were found not to be cytotoxic to no mammals up to 200 mM. Moreover, this study demonstrated that compound 82 was selected to be used in phenotypic studies of drug-treated parasites in order to recognize feasible target organelles. The existence of at least one allyl side chain on the biaryl ether scaffold was essential for antitrypanosomal activity, as demonstrated by structureactivity relationship studies (SARs), and it was also evident that the free phenol was not needed (Scheme 14.8) [49].

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Semisynthesis of Bioactive Compounds and their Biological Activities

Scheme 14.8 Semisynthesis of dehydrodieugenol B and methyldehydrodieugenol B derivatives.

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14.2.9 Semisynthesis of lupeol derivatives Lupeol [lup-20 (29)-en-3b-ol] (95) is a secondary metabolite characterized by its rigidity, lipophilicity, and a relatively high number of stereogenic centers [50,51]. It is classified as a pentacyclic triterpenoid (95) and was successfully isolated from the aerial parts of Vernonia scorpioides, yielding 2.5 g [52]. It is also found in various edible fruits and other traditionally used medicinal plants, such as Bombax ceiba [53]. In 2018, Biavatti et al. used lupeol (95) as the starting material to synthesize 10 lupeol derivatives (96e105). Among these, five novel ester derivatives (101e105) were obtained. The synthesis involved classical procedures including oxidation, reduction, and O-alkylation. The study focused on modifying the isopropylidene fragment of lupeol to generate these novel derivatives (Scheme 14.9) [52]. In vitro antiparasitic studies were carried out on all semisynthetic compounds against amastigote forms of Leishmania amazonensis and Trypanosoma cruzi. A semisynthetic derivative, compound 97, demonstrated the highest antitrypanosomal activity with an IC50 of 12.48 mg/mL and the lowest cytotoxicity with a CC50 value of 161.50 mg/mL.

Scheme 14.9 Semisynthesis of lupeol derivatives.

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Semisynthesis of Bioactive Compounds and their Biological Activities

14.2.10 Semisynthesis of quinoline derivatives The dengue virus (genus Flavivirus) causes dengue fever, an emaciated disease that affects tropical and subtropical regions of the world [9]. In a study conducted by Lleonart et al., two new quinoline derivatives were found to be potent against dengue virus serotype 2 (Scheme 14.10) [54]. Through the TMEDA-catalyzed reaction of 8-hydroxyquinoline N-oxide (106) or the copper-catalyzed reaction of Grignard reagents, 8-hydroxyquinoline N-oxide (106) generated 2-alkylated quinolines 107 and 108. By using N-chlorosuccinimide (NCS) under acidic conditions, the targeted quinolines 109 and 110 were synthesized from compounds 107 and 108, respectively. As they exhibit a wide range of biological activities, quinolines and their derivatives are crucial for the development of drugs with pharmacological properties against a wide range of human pathogens containing viruses [55]. There was a dose-dependent inhibition of dengue virus serotype 2 by two of the studied compounds at low and submicromolar concentrations. In contrast to virucidal compounds, these compounds appear at a very early stage of the viral life cycle and can serve as antiviral agents.

Scheme 14.10 Semisynthesis of quinoline derivatives.

Gonzalez et al. demonstrated the antidengue activity of abietane diterpenoid ferruginous analogs prepared from (þ)-dehydroabietylamine, a commercially available compound in 2016 [56]. Two ferruginous analogs exhibited enhanced antiviral selectivity index and reduced viral plaque size during the postinfection stages against Dengue viruses. One specific derivative showed ten-fold greater potency (EC50 ¼ 1.4 mM) than the control ribavirin against Dengue Virus type 2.

14.2.11 Semisynthesis of aphidicolin derivatives In 2016, Emery et al. conducted a study to achieve the semisynthesis of novel aphidicolin derivatives from the natural tetracyclic diterpene aphidicolin 111. The goal was to develop new drug candidates with potent activity against Trypanosoma cruzi, addressing the limitations of existing treatments

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and aiming for safety, effectiveness, and oral administration [57]. Aphidicolin 111 and 3-deoxy-aphidicolin 112 were obtained from Nigrospora sphaerica cultures [58]. Aphidicolin 111 has a rigid structure with four hydroxyl groups and limited reactivity due to intramolecular interactions, steric hindrance, and low solubility in common organic solvents. These characteristics posed challenges for conventional synthetic approaches [57,59]. To overcome these difficulties, semisynthetic derivatives (113e117) were prepared from natural aphidicolin 111 using oxidation, protection-deprotection methods, oximation, heterocyclization, and acylation. The same investigators previously reported the synthesis of compounds (112e115) (Scheme 14.11) [60]. Compound 115 exhibited an IC50 value of 1.7 mM in Trypanosoma cruzi cells, demonstrating twice the potency of natural aphidicolin 111. Derivatives 116 and 117 displayed a trypanocidal IC50 lower than 1 mM and a selectivity index exceeding 100-fold [57].

Scheme 14.11 Semisynthesis of aphidicolin derivatives.

14.2.12 Semisynthesis of betulin and betulinic acid derivatives Sousa et al. evaluated the anti-Leishmania activity of semisynthetic derivatives derived from natural betulin (118) and betulinic acid (119). The purpose of their study was to further explore the discovery of new, effective, and less

454

Semisynthesis of Bioactive Compounds and their Biological Activities

toxic compounds for the treatment of neglected tropical diseases (NTDs) [61]. Betulin (118) and betulinic acid (119) are pentacyclic lupane-type triterpenes that are widely found throughout the plant kingdom and are commercially derived from plants of Betula species [62]. Previously, novel semisynthetic derivatives of pentacyclic betulin (118) and betulinic acid (119) were synthesized, demonstrating cytotoxic activity against various human cancer cell lines (Scheme 14.12) [63]. The observed cytotoxicity was attributed to apoptosis mechanisms involving caspase signaling and DNA topoisomerase inhibition [64]. These findings prompted the investigators to further explore the potent activity of these derivatives against Leishmania. Within the semisynthetic derivatives, compounds 125 and 126 exhibited notable potency, with IC50 values of 50.8 and 25.8 mM, respectively. These two derivatives represent promising lead compounds that could be utilized in the development of new therapeutic approaches for Leishmania infections, including multidrug treatment strategies involving miltefosine.

Scheme 14.12 Semisynthesis of betulin and betulinic acid derivatives.

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Index ‘Note: Page numbers followed by “f ” indicate figures and “t” indicate tables.’

A 2-Acetoxytrilobolide, 312e314, 335 8ʺ-Acetylobovatin, 118e120 Aconitine-originated lipo-alkaloids, 81 Acylated triterpenes, 373 Additive manufacturing, 426e427 Adenosine derivatives, 315e316 African trypanosomiasis, 441 Afzelin A, 130e134, 133f Alkaloid matrine, 293e294 4a-alkyloxy-2-chloropodophyllotoxin derivatives, 292e293 4a-arylsulfonyloxybenzyloxy-2bchloropodophyllotoxin derivatives, 198 a-mangostin, 298e299 Alzheimer’s disease (AD), 296 Amidochelocardin derivatives, 34e35 Amino acids-modified flavones, 152 Aminomethylatedobovatol derivatives, 187e188 Analgesic drug, 355e361 Angiogenesis, 262, 264 Annonalide derivatives, 296e298 Anthocyanins anticancer activities breast cancer, 262e264 colorectal cancer, 264e266 lung cancer, 260e262 ovarian cancer, 268e269 prostate cancer, 266e268 skin cancer, 269e271 chemical derivatization, 246e259 chemical structure, 244f cyanidin-3-glucoside, 257 cyanidin-3-glucoside-fatty acid lipophilic derivatives, 257 food colorants and additives, 243 malvidin-3-glucoside, 251e252 methylated cyanidin-3-O-glucoside derivatives, 256e257 4-methylfuropelargonidin, 259

methyl pyranoanthocyanin, 254 5-methylpyranopelargonidin, 259 oxovitisins, 255e256 pH effect, 244e246 pyranomalvidin-3-glucoside(+)-catechin pigment, 249e250 pyruvic acid adducts A-D, 252e254 safety issues, 243 stearic ester derivatives, 246e247 vitisins, 247e248 Antibiotics amidochelocardin derivatives, 34 arsinothricin, 31 caprazene derivatives, 43 chemical derivatization, 26e43 classification, 26t clinical applications, 44e50 dialkylresorcinol derivatives, 28 fidaxomicin derivatives, 32 glycopeptides, 39e40 nidulin derivatives, 35e36 platencin thioether derivatives, 26e27 platensimycin (PTM) derivatives, 37e39 resistance mechanism, 25, 26t teicoplanin derivatives, 36e37 unguinol derivatives, 30 Anticancer activities anthocyanins, 259e271 lignans, 199e201 phenolic compounds, 233e234 Antimalarial drug artemisinin, 362e364 artesunate, 365e366 Antimicrobial activity lignans, 203e204 phenolic compounds, 234e235 Antimicrobial resistance, 6e7 Antioxidant activity, 235e236 Apetalrine B, 65e66 neuroprotective effects, 97 structures, 98f Aphidicolin derivatives, 452e453

459

j

460 Aquisiflavoside, 138e140 Arsinothricin, 31 Artemisinin, 316, 362f semisynthetic approach, 364 total synthesis, 364 Artesunate, 365e366 Arylnaphthalene-type lignans, 182, 195e196 Aryltetralin-type lignans, 181 Atorvastatin calcium, 353 Atranorin derivatives, 220 Australian Register of Therapeutic Goods (ARGT), 388 Australian Regulatory Guidance for Complimentary Medicine (ARGCM), 388 Ayurveda, 389e390 Aza-Michael reaction, 281e282

B Barbatusol, 227 Benzofuran lignans, 182e183 Benzoxazole and benzoxazolone derivatives, 188e190 Betalains, 235e236 Betulin and betulinic acid derivatives, 453e454 Bioactive compounds production acylated triterpenes, 373 analgesic drug, 355e361 anticancer drug, 370e372 anti-influenza, 367e368 antimalarial drug, 362e366 cholesterol-lowering drug, 353e354 inhibitory neurotransmitter, 369e370 Biological assessment, 409e411 Blocks-based molecular network (BBMN) strategy, 413 Box-Behnken design, 215 Breast cancer anthocyanins in vitro studies, 263e264 in vivo studies, 262e263 death, 262 Brevicanines A and B, 71e73 Bufospirostenin A, 289 Buprenorphine, 360 Bursehernin, 184e187

Index

C Caprazene (CPZEN), 43e44 Capsamycins, 43 Carvacrol, 221e222 Castration-resistant prostate cancer (CRPC), 267 Cell death, 259e260 Cellulose stearoyl esters, 15 Chafuroside B, 143e144, 146 Chagas disease, 97e98, 439e440 benznidazole (BZN) formulation, 440 dehydrodieugenol B and methyldehydrodieugenol B derivatives, 449 Chikungunya virus (CHIKV), 443e444 Chitosan derivatives, 14e15 Chlorocarbonyl ferrocene, 289e292 15-Chloro-18-oximinoether derivatives, 73e74, 302 4-Chlorophenols, 221 Cholesterol, 293e294 Cholesterol-lowering drug, 353e354 Cinchona alkaloids, 99, 100f Classical molecular networking, 412e413 Codeine, 355e356 Colorectal cancer deaths, 264 in vitro studies, 265e266 in vivo studies, 264e265 Comanthoside, 144 Complementary medicines, 388 Computational chemistry additive manufacturing, 426e427 binding studies, 395e397 computational methods, 401e409 drug repositioning/repurposing, 421e422, 423te424t highest occupied molecular orbitals (HOMOs), 405e409 lowest unoccupied molecular orbitals (LUMOs), 405e409 machine learning, 413e416 molecular electrostatic potential (MESP), 405e406 molecular modeling, 397e399

461

Index

molecular networking, 412e413 network pharmacology, 422e425 rational drug design, 420e421 spectroscopic and X-ray analysis, 399e409 traditional drug design, 419e420 Computer-aided drug design (CADD), 396 Cotylenin A mimic, 320 CRV431, 309e310 Cryptolepine analogs, 443 Cubebin derivatives, 194e195 Curcumin, 14 Cyanidin-3-glucoside, 257e258 Cyanidin-3-glucoside-fatty acid lipophilic derivatives, 257e258 Cycloparviforalone, 296e297

D Dalbavancin, 47e49, 48f Davis oxidation, 280e281 5’’-Deacetylpurpurin, 135e138 Dehydrodieugenol B, 446, 449 Delphinidin, 265e266 Demethylgorgosterol synthesis, 333e334 Demethylsalvicanol, 227 Dengue, 440, 452 quinoline derivatives, 452 serotypes, 440 Dialkylresorcinol derivatives, 28e29 Dibenzocyclooctadiene lignans, 183 Dibenzylbutane-type lignans, 181 Dibenzylbutyrolactone-type lignans, 181 6,8-Dibromogenkwanin, 149e151 Dietary Supplement Health and Education Act (DSHEA), 384 (2S)-2,3-Dihydrotephroapollin C, 135e138 5,7-Dihydroxy-3,6-dimethoxy-2(4-methoxyphenyl)-4Hchromen-4-one, 148 Dimethyldioxirane (DMDO) englerin A synthesis, 340e341 epoxyunguinol and dihydroxyunguinol synthesis, 339e343 polymethoxyflavonoids synthesis, 343 taccalonolide synthesis, 341e342

Discorhabdins, 93e95 Diterpenoid dolabellanes, 443e444 Docetaxel, 9e10 Docking affinity, 397t Dolabellane analogs, 443e445 Dolabellane diterpenes synthesis, 345e346 Drug delivery systems (DDS), 10e15 Drugs and Cosmetics Act, 390

E Ebselen, 10 Ecteinascidin, 85e87, 89 Elenodione, 201f Englerin A synthesis, 340e341 2-Epi-narciclasine, 74e75 Epipolythiodioxopiperazine alkaloids (ETPs), 95e97 Epoxyunguinol and dihydroxyunguinol synthesis, 339e343 Equilenin, 295e296 Ergostane derivative, 407f Ergosterol, 406 Estrogenic activity, lignans, 202 Eugenol derivatives, 221e222 Evodiamine, 68e69

F Ferulic acid, 226e227, 236 Fidaxomicin-ciprofloxacin hybrid, 34 Fidaxomicin derivatives, 32e33 Flavone aliphatic amines-modified, 154 amino acids-modified, 152 chafuroside B, 143e144 semisynthesis, 140e142 Flavonoids acacetin derivatives, 129e130 (2R,3R)-2ʺ-acetyl astilbin, 134e135 acetylated and methylated derivatives, 155e156 8ʺ-acetylobovatin, 118e120 afzelin A, 130e134 anti-obesity activity, 160e167, 163te166t aquisiflavoside, 138e140 biological activities, 160e172

462 Flavonoids (Continued ) chemical derivatization, 140e159 chemistry, 160 5ʺ-deacetylpurpurin, 135e138 6,8-dibromogenkwanin, 149e150 (2S)-2,3-dihydrotephroapollin C, 135e138 (2S)-2,3-dihydrotephroglabrin, 135e138 5,7-dihydroxy-3,6-dimethoxy-2-(4methoxyphenyl)-4H-chromen-4one, 148 glucoside cyclodimer, 120e127 glycosides, 143 hepatoprotective activity, 170e172 5-hydroxy-3,7-dimethoxy-2-(4methoxyphenyl)-4H-chromen-4one, 148e149 hydroxy-7-methoxysaniculamin A, 118e120 5-hydroxy-3,6,7-trimethoxy-2-(4methoxyphenyl)-4H-chromen-4one, 148 icaritin-based antibiotics, 150e153 jaceosidin derivatives, 154 kaempferol-based antimicrobial agents, 145e146 lineaflavones, 118e120 luteolin 7-O-(4ʺ-caffeoyl) bglucopyranoside, 113e115 6-methoxygeraldone, 118e120 natural, 143 neuroprotective activity, 167e170 pharmacological activities, 113 polymethoxyflavonoids, 157 quercetin, methyl ether derivatives, 146e148 rac-6-formyl-5,7-dihydroxyflavanone, 127e129 spectral characteristics, 113e140 structure, 161f 6,6ʺ,3ʺʹ- trihydroxy-7,3ʹ,7ʺ-Otrimethylloniflavone, 116e118 Flavonol glucoside cyclodimer, 120e127 Forodesine, 409e410 Furofuran lignans, 190e192 Fusicoccins, 320

Index

G Galanthamine aromatic esters derivatives, 70e71 7-O-Galloyltricetiflavan (GTF), 7, 140 Ganodermanontriol, 287 GlaxoSmithKline, 419 Glycopeptides, 39e40 Goniomitine, 78e79 Green chemistry, 279 Guaiacol, 221e222 Guanidine derivatives, 99, 100f Guttiferone-A, 231e232

H Hederagenin methyl ester analogs, 447e448 Herbal medicines, 389 Hesperetin derivatives, 170, 171f Hesperidin (HDN), 171e172 2-Hexyl-5-pentylbenzene-1,3-diol, 29 Highest occupied molecular orbitals (HOMOs), 405e409 High throughput automated synthesis chemoselective hydrogenation, 419 PCSK9 inhibitor, 418 Hispidulin, 144 Homolignans, 183 Homoplantaginin, 144 Hydrocodone synthesis, 360e361 Hydrogen peroxide bioactive oxidized products, 338 EDA acid synthesis, 336e337 ocotillol type saponins, 339 oleaceinic acid synthesis, 336e337 oleocanthalic acid synthesis, 336e337 5-Hydroxy-3,7-dimethoxy-2-(4methoxyphenyl)-4H-chromen-4one, 148e149 8-Hydroxymanzamine A, 90e91 Hydroxy-7-methoxysaniculamin A, 118e120 5-Hydroxy-3,6,7-trimethoxy-2-(4methoxyphenyl)-4H-chromen-4one, 148, 150 Hydroxytyrosol, 233e234

463

Index

I Icaritin-based antibiotics, 150e153 Icetexane-based diterpenes, 227e228 Inhibitory neurotransmitter, 369e370 Insecticidal activity lignans, 202e203 2-Iodoxybenzoic acid (IBX) sulfoxide synthesis, 344e345 5,6-tocoquinone synthesis, 343e344

J Jaceosidin derivatives, 154 Jorumycin, 85e87 Juncuenin B derivatives, 217e218, 233 Justicidone, 201f

K Kaempferol-based antimicrobial agents, 145e147 Komaroviquinone pharmacophore, 441

L Lanosterol demethylation, 325 Lanthipeptides, 7e8 Lead compounds, 5f Lecanoric acid derivatives, 219e220 Ligand-based drug discovery (LBDD), 396 Lignans 4a-arylsulfonyloxybenzyloxy-2bchloropodophyllotoxin derivatives, 198 aminomethylatedobovatol derivatives, 187e188 anticancer activity, 199e201 arylnaphthalene lignan derivatives, 195 benzoxazole and benzoxazolone derivatives, 189 bursehernin, 184e187 chemical derivatization, 184e198 cubebin derivatives, 194e195 estrogenic activity, 202 furofuran lignans, 190e192 gastrointestinal tract metabolism, 183e184 insecticidal activity, 202e203 matairesinol dimethyl ether derivatives, 184e187

9-norlignans, 192e194 podophyllotoxin derivatives, 197e198 schisantherin A analogs, 195e197 structures, 182f Limonoid-type derivatives, 301 Linaroside, 144 Lineaflavones, 118e120 Lipo-alkaloids, 80e81 Lipopeptides, 40e41 Liver fibrosis, 171e172 Lumisantonin, 284 Lung cancer anthocyanidins in vitro studies, 261e262 in vivo studies, 260e261 recurrence and metastasis, 260 Lupeol derivatives, 451 Luteolin 7-O-(4ʺ-caffeoyl) b-Dglucopyranoside chemical structure, 114 HR-ESIMS, 114 molecular formula, 114 NMR data, 114, 115t structure determination, 114e115 systematic name, 113 UV and IR, 114

M Machine learning algorithms and applications, 414 data, 415e416 drug discovery steps, 415t encoder and mode, 415e416 molecular fingerprints, 416, 417f natural products, 414 organic synthesis, 415 pharmaceutical industry, 414 Maclekarpine E, 77e78, 317e318 Macrolactam analogs synthesis, 347e348 Makaluvamines, 76 Malvidin-3-glucoside, 251e252 Mannich base derivatives, 200f Manzamine amides, 92e93 Manzamine F, 91e92 Maritidine, 70, 72 Maslinic acid, 1,2,3-triazole derivatives, 311e312

464 Mass spectrometry-based molecular networking, 412 Matairesinol dimethyl ether derivatives, 184e187 Matrine derivatives, 321 Matrinic acids, 293e294 Matrix metalloproteinase-9 (MMP-9), 264 Merrillianone, 296e297 6-Methoxygeraldone, 118e120 5-Methoxypurpurin, 135e138 Methoxystemofoline and analogs, 80e82 Methylated cyanidin-3-O-glucoside derivatives, 256e257 Methyl dehydrodieugenol B, 446e447, 449 4-Methylfuropelargonidin, 259 Methyl pyranoanthocyanin, 254 5-Methylpyranopelargonidin, 259 Michael addition reaction, 281e282 MicroRNAs (miRNAs), 265 Molecular docking studies, 398e399 Molecular electrostatic potential (MESP), 405e406 Molecular modeling, 397e399 Molecular networking, 412e413 Molecular oxygen 2,3-seco-clavine-type ergot alkaloid, 332 unguinol derivatives synthesis, 330e331 Monoamines, 87e93 Morphine annual production and consumption, 355e356, 356f O-alkylated derivatives, 356e357 sulfate esters, 358 Mycotoxins, 187e188

N N-aryl amide analogs of piperine, 442 Natural Health Products Regulations (NHPR), 390 Natural products, 1e2 drug resource, 322 green tools flow chemistry, 309e310 microwave irradiation, 311e314 ultrasound, 314e316

Index

visible light, 316e318 water solvent, 318e321 oxygen atom insertion, metal-free conditions dimethyldioxirane (DMDO), 339e343 hydrogen peroxide, 336e339 2-iodoxybenzoic acid (IBX), 343e345 m-CPBA, 345e348 molecular oxygen, 330e332 ozone, 333e336 targeted microbial transformations, 323e324 room temperature agricultural biotechnology applications, 300e303 bufospirostenin A, 289 chemical derivatization, 280e300 Davis oxidation, 280e281 lignan derivatives, 289e293 Michael addition reaction, 281e282 Norrish type II reaction, 282e284 photosantonin rearrangement, 284e285 Sharpless epoxidation, 285e287 steroid derivatives, 293e296 temperature ranges, 280 terpenoids, 296e298 xanthones, 298e300 Neglected tropical diseases (NTDs) Chagas disease, 439e440 dengue, 440 semisynthesis methods aphidicolin derivatives, 452e453 betulin and betulinic acid derivatives, 453e454 cryptolepine analogs, 443 dehydrodieugenol B and methyldehydrodieugenol B derivatives, 449 dolabellane analogs, 443e445 hederagenin methyl ester analogs, 447e448 lupeol derivatives, 451 methyl dehydrodieugenol B, 446e447 N-aryl amide analogs of piperine, 442 p-quinone analog, 441

465

Index

quinoline derivatives, 452 thiazinoquinone analogue, 448e449 Neolignans, 183 Neomangiferin, 299e300 Network pharmacology, 422e425, 425t Neurodegenerative disorders, 3e4, 169e170 Neuroprotective activity, phenolic compounds, 236e237 Neurotrophins, 296 Nidulin derivatives, 35e36 Nisin, 40e41, 41f, 49e50 Nitric oxide (NO), 10e14 Norlignans, 183, 192e194 Norlobaridone derivatives, 220 Norrish type II reaction, 282e284 Nortrilobolide, 312e313 Nucleoside analogs/derivatives, 409e410 Nutraceuticals classifications, 382e384 clinical data, 383t phytochemicals, 381 regulatory aspects, 382e390 Australia, 388 Canada, 390 China, 389 European Commission, 387 India, 389e390 Japan, 388e389 New Zealand, 387e388 United States of America, 384 side effects, 381e382 terminologies, 382e384

O Obovatol, 6, 8 Ocotillol-type saponin, 339 Oleacein, 230 Oleuropein, 213e214 3-O-methylpancracine, 70e71 Opiates, 355e361 buprenorphine, 360 13 C-labeled, 361 hydrocodone synthesis, 360e361 morphine, 355e356, 358 oxycodone, 358e359 Oritavancin, 47e49

Orsellinic acid derivatives, 220e221 Oseltamivir phosphate, 367e368 Ouabagenin, 282e284 Ovarian cancer anthocyanins in vitro studies, 269 in vivo studies, 268e269 malignant, 268 Oxa-Stork-Danheiser reaction, 280e300 Oxaziridines, 280e281 Oxovitisins, 255e256 (5Z)-7-oxozeaenol, 228e230 Oxycodone, 358e359 Oxystemofoline, 80e82 Ozone 2-acetoxytrilobolide synthesis, 335 demethylgorgosterol synthesis, 333e334 kaurenoic acid and copalic acid, 335e336

P PCSK9 inhibitor, 418 Phenolic compounds, 210f anticancer activity, 233e234 antimicrobial activity, 234e235 antioxidant activity, 235e236 atranorin derivatives, 220 bioactivities, 209, 233e237 carvacrol, 221e222 chemical derivatization, 217e232 eugenol derivatives, 221e222 feed additives, 236 ferulic acid, 226e227 guaiacol, 221e222 guttiferone-A, 231e232 hydroxytyrosolalkylcarbonate derivatives, 222e225 hydroxytyrosolu-hydroxyalkylcarbonate derivatives, 222e225 juncuenin B derivatives, 217e218 lecanoric acid derivatives, 219e220 microwave-assisted extraction algae species, 216 avocado seeds, 216 dried sea buckthorn leaves, 216 green technique, 215 merits, 214 pineapple, 214e215

466 Phenolic compounds (Continued ) response surface methodology (RSM), 216 neuroprotective activity, 236e237 norlobaridone derivatives, 220 oleacein, 230 orsellinic acid derivatives, 221 (5Z)-7-oxozeaenol, 228e230 prenylated resveratrol derivatives, 225 stability, 209e210 stability and recovery, 209e210 thymol, 221e222 ultrasound-assisted extraction, 210e214 black locust flowers, 213 independent variables, 212 mechanism, 211e212 olive leaves, 213e214 solvents, 212e213 Phytopathogenic fungi, 6 Piperine-based hydrazone derivatives, 79e80, 302e303 Plantaginin, 145 Plant alkaloids acetylated makaluvamines, 76 anticancer activity, 56, 57te60t antimicrobial activity, 56, 61te64t apetalrine B, 65 applications, 95e101 biological activities, 55e56 brevicanines A and B, 71e73 15-chloro-18-oximinoether derivatives, 73e74 discorhabdins, 93e95 ecteinascidin, 85e87 2-epi-narciclasine, 74e75 galanthamine derivatives, 71 goniomitine, 78e79 human health, 55e56 indole alkaloids and spondomine, 69e70 jorumycin, 85e87 lipo-alkaloids, 80 maclekarpine E, 77e78 methoxystemofoline, 80e82 monoamines derivative, 87e93 3-O-methylpancracine, 70e71 oxystemofoline, 80e82

Index

piperine-based hydrazone derivatives, 79e80 pseudoceratidine, 83e85 rutaecarpine and evodiamine, 68e69 secondary metabolites, 55 semisynthetic modification, 65e82 verticillin class, 65e66 vittatine and maritidine, 70, 72 Platencin thioether derivatives, 26e27 Platensimycin (PTM) derivatives, 37e39 Podophyllotoxin derivatives, 197e198 esters, 289e292 Polyether ionophores, 49 Polymethoxyflavones, 148e149 Polymethoxyflavonoids, 157e158, 343 p-quinone analog, 441e442 Pregabalin, 369e370 Premarin, 5e6 Prenylated resveratrol derivatives, 225, 235 Propolis, 170 Prostate cancer anthocyanidins in vitro studies, 267e268 in vivo studies, 267 death, 266e267 Protein-ligand scoring functions, 397f Protopanaxadiol (PPD), 338 Puupehenol, 288 Puupehenone, 288 Pyranomalvidin-3-glucoside-(+)-catechin pigment, 249e251

Q Quantitative structure-activity relationship (QSAR) method, 396 Quinazolinone-benzyl piperidine derivatives, 411 Quinoline derivatives, 452

R Rac-6-formyl-5,7-dihydroxyflavanone, 127e129 Rational drug design, 420e421 Resorcinol, 28

467

Index

Response surface methodology (RSM), 216 Riboprine, 409e410 Rosmaridiphenol, 227 Rutaecarpine, 68e69

S Schisantherin A analogs, 195e197, 201 2,3-seco-clavine-type ergot alkaloid, 332e333 Secoisolariciresinoldiglucoside, 183e184 Secondary metabolites, 1e2 Selenium-based drugs, 10 Selenoauraptene, 319 Semisynthetic derivatives applications, 8e10 biological activities, 11te13t Serofendic acid, 3e4, 280e281 Sesamolin, 190, 192 Skin cancer anthocyanins in vitro studies, 270e271 in vivo studies, 270 incidence, 269e270 Stachannin A, 145 Stearic ester derivatives, 246e247 Stemofoline alkaloids and analogs, 314e315 Stigmasterol 13 C-NMR, 401, 402t chemical shifts, 405t 1D and 2D-NMR data, 403te404t DEPT-135 spectra, 401 1 H-NMR, 401, 402t infrared absorption spectrum, 400e401, 401t spectral properties, 400 structure, 400f Structure-based drug discovery (SBDD), 396 Suffranidine A, 413, 413f Sulfoxide synthesis, 344e345 Sustainable chemistry, 309 Suzuki-Miyaura coupling reactions, 416f, 418

T Taccalonolide, 341e342 Taxol, 370e372 Teicoplanin, 36e37, 38t antibacterial activity, 46 carbohydrate residues, 46e47 components, 46f covalent dimers, 49 Telavancin, 47e49, 48f Terpenoids, 296e298 Tetrahydrofuranoid lignans, 182 Tetrahydrofurofuranoid lignans, 182 Therapeutic Goods Administration (TGA), 388 Thiazinoquinone analogue, 448e449 Thymol, 221e222 Thymol-based 1,2,3-triazole hybrids, 318e319 Tigogenin, 284 5,6-Tocoquinone synthesis, 343e344 Topoisomerase (IIB) inhibitors, 410e411 Toxicity, 329 Traditional Chinese Medicine (TCM), 389 Transition-metal-catalyzed transformations, 330 5,7,4ʹ-Triacetoxy jaceosidin, 154 Triazole-coupled analogs, 42 1,2,4-triazole-3-thiones, 99f 6,6ʺ,3ʺʹ-Trihydroxy-7,3ʹ,7ʺ-Otrimethylloniflavone chemical structure, 116 HRESIMS, 117 molecular formula, 116 NMR data, 116, 117t source, 116 structure determination, 117e118 UV and IR, 116 Triple-negative breast cancer (TNBC), 263 Tuberculosis (TB), 335e336

U Unguinol derivatives, 30, 330e331

468

Index

V

W

Vancomycin bacterial infections, 45e46 clinical applications, 45 mechanism of action, 49 Verticillins, 4e5, 65e67, 67t Vinblastine, 99e101 Vinca alkaloids, 101f Vincristine, 99e101 Vinorelbine, 99e101, 102f Vitisins, 247e249 Vittatine, 70, 72

Wilkinson’s catalyst, 289e290

X Xanthatin-amino derivatives, 281e282 Xanthones, 298e300

Z Zika virus (ZIKV), 443e444