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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
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Contents
1. Preliminary concept of semisynthesis and its importance 1

1.1 Introduction 1
1.1.1 Concept of semisynthesis 1
1.1.2 Why do we need semisynthesis? 3
1.1.3 Recent advances in the potential applications of semisynthetic
derivatives 8
1.1.4 Relationship between semisynthesis and drug delivery 10
References 15
2. Semisynthesis of antibiotics 25
2.1 Current antibiotic resistance mechanism 25
2.2 Chemical derivatization of antibiotics 26
2.2.1 Semisynthesis of platencin thioether derivatives 26
2.2.2 Semisynthesis of dialkylresorcinol derivatives 28
2.2.3 Semisynthesis of unguinol derivatives 30
2.2.4 Semisynthesis of arsinothricin 31
2.2.5 Semisynthesis of fidaxomicin derivatives 32
2.2.6 Semisynthesis of amidochelocardin derivatives 34
2.2.7 Semisynthesis of nidulin derivatives 35
2.2.8 Semisynthesis of teicoplanin derivatives 36
2.2.9 Semisynthesis of platensimycin derivatives 37
2.2.10 Semisynthesis of glycopeptides 39
2.2.11 Semisynthesis of lipopeptides 40
2.2.12 Semisynthesis of caprazene derivatives 43
2.3 Recent advances in the clinical applications of antibiotics and their
analogs 44
References 50
3. Semisynthesis of alkaloids 55
3.1 Function of plant alkaloids on human health 55
3.1.1 Anticancer activity of plant alkaloids 56
3.1.2 Antimicrobial activity of plant alkaloids 56
3.2 Semisynthetic modification of alkaloids 65
3.2.1 Semisynthesis of apetalrine B 65
3.2.2 Semisynthesis of promising derivatives of the verticillin class
of natural products 65
v j
vi Contents
3.2.3 Semisynthesis of promising derivatives of rutaecarpine and

evodiamine 68
3.2.4 Semisynthesis of (þ)- and ()-spondomine and stereoisomers 69
3.2.5 Semisynthesis of esters of galanthamine,
3-O-methylpancracine, vittatine, and maritidine 70
3.2.6 Semisynthesis of brevicanines A and B 71
3.2.7 Semisynthesis of 15-chloro-18-oximinoether derivatives 73
3.2.8 Semisynthesis of 2-epi-narciclasine 74
3.2.9 Semisynthesis of acetylated makaluvamines 76
3.2.10 Semisynthesis of the analogs of maclekarpine E 77
3.2.11 Semisynthesis of (þ)-goniomitine 78
3.2.12 Semisynthesis of piperine-based hydrazone derivatives 79
3.2.13 Semisynthesis of lipo-alkaloids 80
3.2.14 Semisynthesis of oxystemofoline, methoxystemofoline and
analogs 80
3.3 Semisynthesis of bioactive marine alkaloids 82
3.3.1 Semisynthesis of N12-acetylpseudoceratidine,
N12-formylpseudoceratidine, N-methylpseudoceratidine
and pseudoceratidine azido derivatives 83
3.3.2 Semisynthesis of antitumor drug Ecteinascidin 743 and
()-Jorumycin 85
3.3.3 Semisynthesis of monoamines derivative 87
3.3.4 Semisynthesis of discorhabdins P and U and analogs of
discorhabdin C 93
3.4 Recent progress in semisynthesis and potential applications of
semisynthetic alkaloid derivatives 95
References 102
4. Semisynthesis of flavones 113

4.1 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-L-
rhamnopyranosyl(1000 /600 )]-b-D-glucopyranoside (12), acacetin-7-O-
[60000 -O-acetyl-b-Dglucopyranosyl(10000 /200 )-3000 -O-acetyl-a-L-
rhamnopyranosyl(1000 /600 )]-b-D-glucopyranoside (13) and acacetin-7-
O-[30000 ,60000 -di-O-acetyl-b-D-glucopyranosyl(10000 /200 )-4000 -O-acetyl-
a- L - rhamnopyranosyl(1000 /600 )]-b-D-glucopyranoside (14) 129
Contents vii
4.1.7 Afzelin A (15) 130

4.1.8 (2R,3R)-200 -acetyl astilbin (16) 134
4.1.9 (þ)-500 -deacetylpurpurin (17), (þ)-5-methoxypurpurin (18),
(2S)-2,3-dihydrotephroglabrin (19), and (2S)-2,3-dihydroteph
roapollin C (20) 135
4.1.10 Aquisiflavoside (21) 138
4.2 Chemical derivatization of flavonoids 140
4.2.1 Semisynthesis of flavone hybrids 140
4.2.2 Semisynthesis of natural flavonoids and flavonoid glycosides 143
4.2.3 Semisynthesis of chafuroside B, a C-glycosylated bioactive
flavone 143
4.2.4 Semisynthesis of kaempferol-based antimicrobial agents 145
4.2.5 Semisynthesis of methyl ether derivatives of quercetin 146
4.2.6 Semisynthesis of 5,7-dihydroxy-3,6-dimethoxy-2-
(4-methoxyphenyl)-4H-chromen-4-one and 5-hydroxy-3,7-
dimethoxy-2-(4-methoxyphenyl)-4H-chromen-4-one 148
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-(4-
methoxyphenyl)-4H-chromen-4-one 148
4.2.8 Semisynthesis of 6,8-dibromogenkwanin 149
4.2.9 Semisynthesis of icaritin-based antibiotics 150
4.2.10 Semisynthesis of 5,7,40 -triacetoxy jaceosidin, 5,7,40 -
tripivaloyloxy jaceosidin, and 5,7,40 -trimethoxy jaceosidin 154
4.2.11 Semisynthesis of acetylated and methylated derivatives of
flavonoids 155
4.2.12 Semisynthesis of polymethoxyflavonoids 157
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, 8-
dimethylaminocasticin 158
4.3 Chemistry and biological activities of flavonoids and their analogs 160
4.3.1 Chemistry of flavonoids 160
4.3.2 Biological activities of flavonoids and their analogs 160
References 172
5. Semisynthesis of lignans 181

5.1 Gastrointestinal tract metabolism of lignans in humans 183
5.2 Chemical derivatization of lignans 184
viii Contents
5.2.1 Semisynthesis of bursehernin and matairesinol dimethyl

ether derivatives 184
5.2.2 Semisynthesis of aminomethylated obovatol derivatives 187
5.2.3 Semisynthesis of benzoxazole and benzoxazolone derivatives 188
5.2.4 Semisynthesis of furofuran lignans 190
5.2.5 Semisynthesis of 9-norlignans 192
5.2.6 Semisynthesis of cubebin derivatives 194
5.2.7 Semisynthesis of arylnaphthalene lignan derivatives 195
5.2.8 Semisynthesis of schisantherin A analogs 195
5.2.9 Semisynthesis of podophyllotoxin derivatives 197
5.2.10 Semisynthesis of 4a-arylsulfonyloxybenzyloxy-
2b-chloropodophyllotoxin derivatives 198
5.3 Recent developments in the bioactivities of semisynthetic lignan analogs 199
5.3.1 Anticancer activity of semisynthetic lignan analogs 199
5.3.2 Estrogenic activity of semisynthetic lignan analogs 202
5.3.3 Insecticidal activity of semisynthetic lignan analogs 202
5.3.4 Antimicrobial activity of semisynthetic lignan analogs 203
References 204
6. Semisynthesis of phenolic compounds 209

6.1 Merits of ultrasound-assisted extraction of phenolic compounds 210
6.1.1 The mechanism of ultrasound-assisted extraction of
phenolic compounds 211
6.1.2 Ultrasound-assisted extraction of phenolic compounds 212
6.2 Microwave-assisted extraction of phenolic compounds 214
6.3 Chemical derivatization of phenolic compounds 217
6.3.1 Semisynthesis of racemic and enantiomerically pure chiral
juncuenin B derivatives 217
6.3.2 Semisynthesis of lecanoric acid, atranorin, norlobaridone, and
orsellinic acid derivatives 219
6.3.3 Semisynthesis of thymol, carvacrol, guaiacol, and eugenol
derivatives 221
6.3.4 Semisynthesis of hydroxytyrosol u-hydroxyalkylcarbonate
derivatives and hydroxytyrosol alkylcarbonate derivatives 222
6.3.5 Semisynthesis of prenylated resveratrol derivatives 225
6.3.6 Semisynthesis of ferulic acid derivatives 226
6.3.7 Semisynthesis of barbatusol, demethylsalvicanol, and
rosmaridiphenol 227
6.3.8 Semisynthesis of (5Z)-7-oxozeaenol analogues 228
6.3.9 Semisynthesis of oleacein from oleuropein 230
Contents ix
6.3.10 Semisynthesis of novel derivatives of natural guttiferone-A

(LFQM-79, LFQM-80, LFQM-81, LFQM-82, LFQM-113 and
LFQM-114) 231
6.4 Recent advances in the bioactivities of semisynthetic derivatives
of phenolic compounds 233
6.4.1 Anticancer activity of semisynthetic derivatives of phenolic
compounds 233
6.4.2 Antimicrobial activity of semisynthetic derivatives of
6.4.3 Antioxidant activity of semisynthetic derivatives of phenolic
compounds 235
6.4.4 Semisynthetic derivatives of phenolic compounds as
efficient feed additives 236
6.4.5 Neuroprotective activity of semisynthetic derivatives of
References 237
7. Semisynthesis of anthocyanins 243

7.1 Anthocyanins as food colorants and additives 243
7.2 The effect of pH on the chemical structure of anthocyanins 244
7.3 Chemical derivatization of anthocyanins 246
7.3.1 Semisynthesis of stearic ester derivatives 246
7.3.2 Semisynthesis of type A vitisins and type B vitisins 247
7.3.3 Semisynthesis of pyranomalvidin-3-glucoside-(þ)-catechin
pigment 249
7.3.4 Semisynthesis of [30 -O-methyl-3H]malvidin-3-glucoside 251
7.3.5 Semisynthesis of anthocyanin-pyruvic acid adducts A-D 252
7.3.6 Semisynthesis of methyl pyranoanthocyanin 254
7.3.7 Semisynthesis of oxovitisins 255
7.3.8 Semisynthesis of methylated cyanidin-3-O-glucoside derivatives 256
7.3.9 Semisynthesis of cyanidin 3-(600 -benzoyl)-glucoside, cyanidin
3-(600 -salicyloyl)-glucoside and cyanidin 3-(600 -cinnamoyl)-
glucoside 257
7.3.10 Semisynthesis of cyanidin-3-glucoside-fatty acid lipophilic
derivatives 257
7.3.11 Semisynthesis of 5-methylpyranopelargonidin and
4-methylfuropelargonidin 259
7.4 Anticancer activities of anthocyanidins and their derivatives 259
7.4.1 Lung cancer 260
7.4.2 Breast cancer 262
x Contents
7.4.3 Colorectal cancer 264

7.4.4 Prostate cancer 266
7.4.5 Ovarian cancer 268
7.4.6 Skin cancer 269
References 271
8. Semisynthesis of natural products at room temperature 279

8.1 Room-temperature chemical transformations: a concept 279
8.2 Chemical derivatization of natural products at room temperature 280
8.2.1 Davis oxidation or Davis oxaziridine oxidation at room
temperature 280
8.2.2 Michael addition reaction at room temperature 281
8.2.3 Norrish type II reaction at room temperature 282
8.2.4 Photosantonin rearrangement at room temperature 284
8.2.5 Sharpless epoxidation at room temperature 285
8.2.6 Oxa-StorkDanheiser reaction at room temperature 287
8.2.7 Semisynthesis of ()-bufospirostenin A using Wilkinson’s
catalyst at room temperature 289
8.2.8 Semisynthesis of lignan derivatives at room temperature 289
8.2.9 Semisynthesis of steroid derivatives at room temperature 293
8.2.10 Semisynthesis of terpenoids derivatives at room temperature 296
8.2.11 Semisynthesis of xanthones at room temperature 298
8.3 Potential agricultural biotechnology applications of semisynthetic
derivatives 300
References 303
9. Semisynthesis of natural products under greener conditions 309

9.1 Concept of sustainability 309
9.2 Semisynthesis of natural products using green tools 309
9.2.1 Semisynthesis of CRV431 using flow chemistry as a green tool 309
9.2.2 Semisynthesis of natural products using microwave irradiation
as a green tool 311
9.2.3 Semisynthesis of natural products using ultrasound as a green
tool 314
9.2.4 Semisynthesis of natural products using visible light as a green
tool 316
9.3 Semisynthesis of natural products using water as a green solvent 318
9.3.1 Semisynthesis of thymol-based 1,2,3-triazole hybrids 318
9.3.2 Semisynthesis of selenoauraptene 319
9.3.3 Semisynthesis of a cotylenin A mimic 320
Contents xi
9.3.4 Semisynthesis of novel matrine derivatives 321

9.4 Sustainability of natural products as a drug resource 322
9.5 Targeted microbial transformations 323
References 325
10. Semisynthesis of natural products through the insertion of

oxygen atom under metal-free conditions 329
10.1 Concept of toxicity 329
10.2 Merits of metal-free reactions 330
10.3 Semisynthesis of different natural products via insertion of the
oxygen atom 330
10.3.1 Semisynthesis using molecular oxygen (O2) 330
10.3.2 Semisynthesis using ozone (O3) 333
10.3.3 Semisynthesis using hydrogen peroxide (H2O2) 336
10.3.4 Semisynthesis using dimethyldioxirane (DMDO) 339
10.3.5 Semisynthesis using 2-iodoxybenzoic acid (IBX) 343
10.3.6 Semisynthesis using m-CPBA 345
References 348
11. Adaptation of organic reactions in the industrial production

of bioactive compounds 353
11.1 Cholesterol-lowering drug 353
11.1.1 Atorvastatin calcium 353
11.1.2 A green-by-design biocatalytic procedure for the
synthesis of atorvastatin intermediate 354
11.2 Analgesic drug 355
11.2.1 Opiates 355
11.3 Antimalarial drug 362
11.3.1 Artemisinin and its derivatives 362
11.3.2 Simplified and efficient synthesis of artesunate 365
11.4 Anti-influenza 367
11.4.1 Oseltamivir phosphate 367
11.5 Inhibitory neurotransmitter 369
11.5.1 Pregabalin 369
11.6 Anticancer drug 370
11.6.1 TaxolÒ 370
11.7 Miscellaneous 373
11.7.1 Preparation of acylated triterpenes (oleanolic acid and
maslinic acid) from olive-oil industry wastes 373
References 374
xii Contents
12. New derivatives as nutraceuticals: regulatory considerations 381

12.1 Nutraceuticals 381
12.2 Regulatory Aspects 382
12.2.1 Terminologies, classifications, and preliminary concepts 382
12.2.2 Regulatory aspects in the United States of America 384
12.2.3 Regulatory aspects in the European Commission 387
12.2.4 Regulatory aspects in New Zealand 387
12.2.5 Regulatory aspects in Australia 388
12.2.6 Regulatory aspects in Japan 388
12.2.7 Regulatory aspects in China 389
12.2.8 Regulatory aspects in India 389
12.2.9 Regulatory aspects in Canada 390
References 391
13. Computational chemistry of natural product analogues 395

13.1 Binding studies 395
13.2 Molecular modeling 397
13.3 Spectroscopic and X-ray analysis of active sites 399
13.3.1 Spectral properties of stigmasterol 400
13.3.2 Infrared absorption spectrum of stigmasterol 400
13.3.3 1H-NMR, 13C-NMR and DEPT-135 spectra of stigmasterol 401
13.3.4 Computational methods 401
13.4 Strategies in biological assessment 409
13.5 Molecular networking 412
13.6 Machine learning for target identification and synthesis 413
13.7 High throughput automated synthesis and testing 416
13.7.1 Application of high-throughput experimentation 418
13.8 An overview of existing databases and their use in rational drug design 419
13.8.1 Challenges associated with traditional drug design 419
13.8.2 Rational drug design 420
13.9 Repurposing of targeted drugs 421
13.10 Network pharmacology 422
13.11 3D printing of reactionware (additive manufacturing) 426
References 427
14. Developing semisynthesis methods for neglected tropical

diseases 439
14.1 Brief overview of neglected tropical diseases (NTDs) 439
14.2 Development of semisynthesis methods for neglected tropical diseases 440
Contents xiii
14.2.1 Semisynthesis of p-quinone analog containing

komaroviquinone pharmacophore 441
14.2.2 Semisynthesis of N-aryl amide analogs of piperine 442
14.2.3 Semisynthesis of cryptolepine analogs 443
14.2.4 Semisynthesis of dolabellane analogs 443
14.2.5 Semisynthesis of methyl dehydrodieugenol B 446
14.2.6 Semisynthesis of hederagenin methyl ester analogs 447
14.2.7 Semisynthesis of thiazinoquinone analogue thiazoavarone 448
14.2.8 Semisynthesis of dehydrodieugenol B and
methyldehydrodieugenol B derivatives 449
14.2.9 Semisynthesis of lupeol derivatives 451
14.2.10 Semisynthesis of quinoline derivatives 452
14.2.11 Semisynthesis of aphidicolin derivatives 452
14.2.12 Semisynthesis of betulin and betulinic acid derivatives 453
References 455
Index 459
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 dis-
eases [1,2]. Natural products are mainly featured by various scaffolds, struc-
tural 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 calcu-
lated octanol-water partition coefficients, the presence of stereogenic cen-
ters, 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 protein-
protein interactions [8]. Secondary metabolites are important for drug devel-
opment 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 character-
ization 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 appli-
cations 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

© 2024 Elsevier Inc.
j
ISBN: 978-0-443-15269-6
https://doi.org/10.1016/B978-0-443-15269-6.00011-0 All rights reserved. 1
2 Semisynthesis of Bioactive Compounds and their Biological Activities
synthesis is necessary [12,14]. Semisynthetic derivatives are frequently

preferred due to their enhanced activity or toxicity profiles [15]. It is neces-
sary 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 de-
rivatives are valuable sources of novel drug candidates with diverse pharma-
cological properties [5,16,17]. Living organisms are great chemical factories
that can construct structurally-complex secondary metabolites by biosyn-
thesis 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 function-
alization reactions, ring-forming reactions, and skeletal rearrangement pro-
cesses 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 mole-
cules. 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, be-
tween 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 semi-
synthetic 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 mod-
ifications 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 intro-
ducing the acetyl group and necessary sidechain by a series of steps
[22,23]. Using microbially-derived artemisinic acid as the synthetic precur-
sor, 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 3
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 approx-
imately 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 bac-
terial 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]. Conse-
quently, 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 ana-
logs, which plays an important role in drug discovery and development [12].
For researchers, students, and the next generations, the concept of semisyn-
thesis 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, exem-
plify this phenomenon [33]. In the United States, severe and chronic neuro-
degenerative 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 pro-
grammed cell death. As cells in the central nervous system have limited
regenerative capabilities, this tissue damage is irreversible. Neurodegenera-

tive diseases are drug-poor and therefore have limited access to clinically
accepted therapeutics. Several studies have shown that the natural diterpe-
noid serofendic acid provides neuroprotection against mechanisms of cell
death associated with this disease. It is highly potent and shows neuroprotec-
tive effects at nanomolar concentrations [35]. Serofendic acid has demon-
strated promising results in preclinical studies, but its development has
been limited due to the lack of an adaptable source for this animal-
derived natural product. Fetal calf serum contains trace amounts of serofen-
dic 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 com-
pound 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 cytotox-
icity [43]. The epipolythiodioxopiperazine alkaloid verticillin A (2) demon-
strated 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, semisyn-
thesis plays an important role in overcoming the limitations of verticillin
A (2) and related compounds, particularly their poor solubility and optimi-
zation to investigate the structure-activity relationship (SAR) through struc-
tural 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 ver-
ticillin H (3). As verticillins have limited solubility, adding these groups may
increase their drug properties, such as cell permeability [44]. In addition, lit-
tle research has been conducted on their mode of binding. The bridged
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 mole-
cule 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, equi-
lenin, 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 equile-
nin and equilin these substances are still extracted from the urine of pregnant
mares. At the same time, estrone is synthesized on an industrial scale by

chemical synthesis. Premarin contains three active ingredients that are deriv-
atives 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 protec-
tants 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 struc-
tural skeletons [59]. From natural lignan obovatol (5), Cao et al. produced
several Mannich base derivatives with potential antifungal activity by modi-
fying 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 resis-
tance is among the greatest threats to human and animal health, food secu-
rity, 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].
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 com-
pound 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 con-
tains seven phenolic hydroxyl groups and is known for its anti-oxidant
and neuroprotective properties, which have been linked to preventing Alz-
heimer’s disease [67]. However, like most natural flavonoids, 7-O-galloyltri-
cetiflavan (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 hy-
droxyl groups in 2020 (Chapter 4, Scheme 4.1) [69].
Lanthipeptides are known as lantibiotics; Gram-positive bacteria pro-
duce 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 struc-
tures of the lantibiotics, namely nisin (8). The peptide nature of nisin (8)
also poses some limitations, including susceptibility to proteolytic degrada-
tion 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
lipopeptides are attractive candidates for further development as new antibi-

otics (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 semisyn-
thetic 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 deriv-
atives 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 lead-
ing 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 chal-
lenging [78]. There is still a need for drug invention and improvement ef-
forts 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 co-
workers 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
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 podophyllo-
toxin, 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 ana-
logs with higher pharmacological activity and fewer side effects [86]. Teni-
poside, 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 anti-
cancer agents that inhibit topoisomerase I [88,89]. Several semisynthetic nat-
ural 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 anti-
cancer 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
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 anti-
cancer properties [93]. Selenium-based drugs have demonstrated promise as
orally active treatments for conditions such as hypertension, infections, can-
cer, and immune system suppression in various diseases [94]. Ebselen, a syn-
thetic 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 co-
workers 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 an-
imals; 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 degra-
dation 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
Table 1.1 Developments in the biological activities of semisynthetic derivatives.
Preliminary concept of semisynthesis and its importance

Bioactivity of
Starting natural product Semisynthetic semisynthetic
(class) Source (family) derivatives derivatives References
Annonalide Casimirella (icacinaceae) Nine analogs Antitumor [99]

(diterpenoid)
Callitrisic acid Callitris columellaris F. Jiadifenoic acid C Antiviral [100]
(diterpenoid) Muell (Cupressaceae)
CDCHD (2- Amycolatopsis sulphurea Twenty-two analogs Antibacterial [101]
carboxamido-2- (Pseudonocardiaceae)
deacetyl-chelocardin)
(antibiotic)
Columbin (diterpenoid) Jateorhiza columba Eight analogs KOR (kappa-opioid [102]
(Menispermaceae) receptor) activity
Honokiol (neolignan) Magnolia officinalis Thirty-seven analogs Insecticidal [103]
(Magnoliaceae)
Hydroxytyrosol Olive oil (Oleaceae) Ten analogs Trypanocidal and [104]
(phenol) cytotoxic
Kirenol (diterpenoid) Siegesbeckia orientalis Seven analogs FXa inhibition [105]
(Compositae)
Lupeol (triterpenoid) Bombax ceiba Five analogs Skin recovery activity [106]
(Bombacaceae)
Macrocarpal A Eucalyptus globulus Macrocarpal C Antibacterial and [107]
(diterpenoid) (Myrtaceae) antiviral
Mangiferin (xanthone) Gentiana asclepiadea L. Neomangiferin Hypoglycemic [108]
(Gentianaceae)
(Continued)
11
Table 1.1 Developments in the biological activities of semisynthetic derivatives.dcont'd
12
Bioactivity of
Starting natural product Semisynthetic semisynthetic
(class) Source (family) derivatives derivatives References
Matrine (alkaloid) Sophora alopercuroides L. Sophocarpine Antinociceptive, [109]
(Fabaceae) anticancer, and anti-
inflammatory
Maslinic acid Olea europaea L. Seven triazole analogs Herbicide [110]
(triterpenoid) (Oleaceae)

Morelloflavone Garcinia Three derivatives Leishmanicidal, anti- [111]
(flavonoid) Brasiliensis proteolytic, anti-
(Guttiferae) oxidant activities and
low cytotoxicity also.
Narciclasine (alkaloid) Narcissus pseudonarcissus 2-epi narciclasine, Acetylcholinesterase [112]
(Amaryllidaceae) narciprimine inhibitor
Obovatol (lignan) Magnolia obovata Thunb Twenty-one analogs Antifungal [60]
(Fabaceae)
Oleuropein (phenol) Olea europaea (Fabaceae) Oleacein Anti-inflammatory [113]
Ostiole (coumarin) Cnidium monnieri Thirty-one analogs Larvicidal [114]
(Apiaceae)
Rottlerin (phenol) Mallotus philippensis Four analogs Cytotoxic [115]
(Euphorbiaceae)
Saponin A (saponin) Uncaria rhynchophylla Uncaring acid C Inhibitor of Ab42 [116]
(Rubiaceae) aggregation
Secotrichagmalin Trichilia connaroides Twelve analogs Cytotoxic [117]
(triterpenoid) (Meliaceae)
Tocopherol (vitamin) Soybean (Fabaceae) Fifteen analogs Cytotoxic and [118]
antibacterial
Preliminary concept of semisynthesis and its importance
Toosendanin Melia azedarach Twelve analogs Insecticidal [119]
(triterpenoid) (Meliaceae)
Ursolic and betulinic Malus domestica and Twenty-four analogs Antimalarial and [120]
acid (triterpenoid) Platanus acerifolia cytotoxic
(Rosaceae and
Platanaceae)
Withanolide D (steroid) Withania somnifera L. Twenty-five analogs Cytotoxic [121]
(Solanaceae)
13
properties, by blending, crosslinking, or grafting [124]. Often, natural poly-

mers are synthetically modified to change or enhance their properties [125].
Semisynthetic polymers, therefore, have the potential to overcome the lim-
itations 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 gov-
erned 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 nano-
particles. Dermal evaluations have been conducted on murine models.
Incorporating these systems has been shown to improve the physicochem-
ical 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 unpro-
cessed 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 cur-
cumin and genistein, Ko and his colleagues fabricated curcumin and/or
genistein-encapsulated nanostructured lipid carriers. A co-loading of curcu-
min and genistein did not adversely affect their solubility and stability. A
chemical modification of curcumin’s chemical structure improves its anti-
cancer 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 pros-
tate cancer cell lines, the analogue induces apoptosis and inhibits cell prolif-
eration 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
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 mod-
ifications, novel polymeric materials were developed with various biophar-
maceutical and physicochemical properties, such as solubility, pH sensitivity,
adsorption, and thermostability [138,139]. Chemical modifications of chito-
san include thiolation, succinylation, carboxymethylation, grafting, and
copolymerization. The amine groups of chitosan were coupled with carbox-
ylic 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 elec-
trostatic 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, probi-
otics 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 nonste-
roidal 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 dis-
eases pose a significant threat to humans. With the discovery of antibiotics,
there was optimism that infections could be prevented and controlled. How-
ever, 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 oc-
curs when bacteria change in response to the application of antibiotics; to pre-
vent 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 methicillin-
resistant 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” mean-
ing against and “biotikus” meaning fit for life). Hence, antibiotic means “life-
killing”. The appearance of antibiotic resistance in pathogenic bacteria has
become the main warning to worldwide public health. Understanding the mech-
anism 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 mecha-
nism of action, Table 2.1 represents the various antimicrobial groups [8e10].
Table 2.2 provides antimicrobial resistance mechanisms in Staphylococcus
aureus [11].

© 2024 Elsevier Inc.
j
ISBN: 978-0-443-15269-6
https://doi.org/10.1016/B978-0-443-15269-6.00007-9 All rights reserved. 25
Table 2.1 A classification of antimicrobials based on their mode of

action.
Antimicrobial groups Mechanism of action
Tetracyclines Inhibit protein synthesis

Chloramphenicol
Oxazolidinones
Lincosamides
Penicillins Inhibit cell wall synthesis
Cephalosporins
b-Lactams
Monobactams
Fluoroquinolones Inhibit the nucleic acid synthesis
Quinolones
Lipopeptides Depolarize cell membrane
Trimethoprim Inhibit metabolic pathways
Sulfonamides
Table 2.2 Types of antimicrobial resistance mechanisms of

Staphylococcus aureus.
Antimicrobial agents Resistance mechanism
Chloramphenicol Drug inactivation

b-Lactams
Tetracyclines
Glycopeptides Limiting the intake of drugs
Fluoroquinolones Active drug efflux
Streptogramins Modification of drug target
Tetracyclines
Lipopeptides
Macrolides
b-Lactams
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 anti-
biotic 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 Strep-
tomyces platensis MA7339 in Spain [14]. The tricyclic cage unit of platencin
(1) is biosynthesised from an ent-atiserene precursor and a 3-amino-2,4-
dihydroxybenzoic acid moiety, both of which can interact with FabF (crit-
ical 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 tet-
rabutylammonium fluoride (TBAF) in DCM and LiOH (2 M) to yield pla-
tencin oxirane (2) as a single isomer with high regioselectivity at room
temperature via oxidation reaction in 90% yield. The presence of a stereo-
hindered 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 thi-
oether 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 halogen-
containing 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 concentra-
tions (MICs) of 1e2 mg/mL against various S. aureus strains [13].
Scheme 2.1 Semisynthesis of platencin thioether derivatives.

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 com-
pounds, 5-heptyl-2-hexylresorcinol (17) and 2-hexyl-5-pentylresorcinol
(18), from the bacterium Pseudomonas aurantiaca YM03-Y3, and have pre-
pared 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 5-
heptyl-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 monofluoro-
sulfated 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-5-
pentylresorcinol (18) showed better antimicrobial activity [21] due to a
shorter alkyl side chain.
Scheme 2.2 Semisynthesis of dialkylresorcinol derivatives.
Scheme 2.3 The chemical structures of semisynthetic derivatives of 2-hexyl-5-

pentylbenzene-1,3-diol (18).
2.2.3 Semisynthesis of unguinol derivatives
By cultivating Aspergillus unguis on a large scale, it is possible to obtain dep-
sidone unguinol (40), the organism’s main metabolite [22]. The semisynthe-
sis 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, partic-
ularly against Staphylococcus aureus [23].
Ten second-generation 3-O-benzylated derivatives (41aej) were ob-
tained by treating unguinol (40) with benzyl bromide at 50 C (Scheme
2.4). Three picolyl derivatives (41k-m) were obtained by combining dep-
sidone 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-(2-
chloroethyl) morpholine, 1-(2-chloroethyl) pyrrolidine, and 1-(2-
chloroethyl) 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.

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 arsino-
thricin (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. devel-
oped 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.

2.2.5 Semisynthesis of fidaxomicin derivatives

Glycosylated macrocyclic lactone fidaxomicin (47, tiacumicin B) was pro-
duced from actinomycetes, and four different soil bacteria also produced
this macrolide antibiotic (47) [27,28]. Fidaxomicin (47), an atypical anti-
biotic, 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 wa-
ter 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 medic-
inal 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 -hydrox-
yl 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 con-
verted into the corresponding bromoacetyl-ciprofloxacin 58 in the presence
of the bromoacetyl bromide and compound 58 was reacted with fidaxomi-
cin (47) in basic conditions (K2CO3 in DMF) to afford desired hybrid 59
(Scheme 2.7). The fidaxomicinrifampicin hybrid was also synthesized.
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Title: Ludwig Richter-Büchlein: Mit vielen schönen Holzschnitten

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RICHTER-BÜCHLEIN: MIT VIELEN SCHÖNEN HOLZSCHNITTEN
DES MEISTERS: VON HAUS UND HOF WEIB KIND UND KEGEL
***
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Ludwig Richter-Büchlein
Mit vielen schönen Holzschnitten
des Meisters: von Haus und Hof
Weib Kind und Kegel
Mit volkstümlichen Gedichten

Erschienen im Einhorn-Verlag in Dachau
Die Welt Ludwig Richters
Wenn die Erinnerung den Weg in meine Jugend zurückgeht, kehrt
sie in einer alten Mühle ein, in der ich meine schönsten Kindertage
verlebt habe. Durch den Torbogen sieht man die Säcke aufgetürmt
im kühlen Hausflur liegen, das Wasser stürzt und feiner Staub erfüllt
die Luft. Dort geschah es manchmal, wenn wir Kinder hoch oben auf
den Säcken spielten, daß ein Handwerksbursche in den Torbogen
trat und unbekümmert ins Haus hineinrief: „Grüß Gott, wandernder
Müller.“ Wenn dann der Müller, oder seine Frau, herbeikamen und
ihm als Zunftgenossen den üblichen Reisenickel gegeben hatten,
erzählte er noch einiges vom Woher und Wohin, und daß er sich nun
das Saaltal aufwärts übern Wald nach Franken durchschlagen wolle,
bis zu den Alpen. — Das ist lange her, aber damals erwachte die
Wanderlust und Wandersehnsucht in mir, und wenn die ersten
blauen Frühlingstage kommen, geht die Erinnerung noch heute
freudig und sehnsüchtig zurück zu der Mühle in der kleinen Stadt
und zu dem wandernden Müller, der über’n Wald nach Franken
wollte, bis zu den Alpen. Die Welt, in der die Mühle stand, war die
Welt Ludwig Richters; die Mühle mit ihren winkligen Neben-Häusern
und Höfen, wo man dem Nachbar in den Kochtopf sehen konnte und
wo sich ein behagliches Reich von Hinterhäusern auftat, mit Höfen
und Höfchen, mit eifrigen Tauben und bunt blühenden
Fenstergärtchen, mit Scheunen, wo man das Dreschen hörte, und
Hausgärten, die bis zum Stadtgraben gingen; dort drängten im
ersten Frühjahr die Schneeglöckchen aus dem Rasen und im Herbst
warfen die alten, schönen deutschen Rosenbüsche ihre Blätter auf
die Wege. Und waren die Einfassungen aus Buxbaum auch etwas
schadhaft und die Gartenlaube windschief, so erging sich doch Groß
und Klein in dem Garten, die Frauen schwatzten an den
Nachbarzäunen und nirgends in der Welt war es behaglicher. — So
war die ganze Stadt: am Samstag kamen die Marktweiber in
strengen schwarzen Kopftüchern von ihren Dörfern mit Tragkörben
und Butterkübeln aus weißgescheuertem Tannenholz auf dem
Rücken zum Markt, wo wir Kinder uns in der Sonne zwischen den
Körben und Obstständen herumtrieben und die Leute vor den
Fleischerbuden standen und rötlichen Landwein zu ihren
Bratwürsten tranken; da war gut sein: warme Sonne, leichter blauer
Rauch von den Bratrosten, Musik vom Rathausturm, dazu fröhlicher
Kleinstadtlärm und dazwischen bummelnde Studenten, die sich für
eine Spritzfahrt auf die Bierdörfer talauf, talab verabredeten.
Wenn dann die Nacht kam, waren die Straßen leer und bei
Mondschein brannte auf Geheiß der sparsamen Obrigkeit keine
Laterne; Gassen und Häuser lagen kühl und still: kaum das Fallen
des Wassers in die Steintröge, das Schlagen eines letzten Fensters,
die gedämpfte Fröhlichkeit der trinkenden Philister hinter
verhangenen Gasthausfenstern und das Stundenblasen des
Türmers vom Turme der Stadt. Und der Fremde, der durch ein
Stadttor hereinkam und in den Häuserschatten durch die Straßen
ging, der hörte nichts als etwa ein Flüstern in einem Türbogen und
das nächtliche Rauschen des Fluß-Wehres, wenn der Wind vom
Tale herkam.
Das alles ist anders geworden und nicht viele wissen noch
davon; auch die Volksfeste und Jahrmärkte sind anders geworden,
wo lange Schaftstiefel und noch fast neue Anzüge in wackeligen
Buden baumelten, wo die geblähten, ewig unruhigen Zelte der
Tausendkünstler und Seiltänzer standen mit ihrem geheimnisvollen
Leben und den Gaffern davor, und dann — die Buden voll
Pfefferkuchen und Türkenhonig und Zuckerzeug, rotem und grünem!
Damals hatte die Zeit sich noch nach den Volksfesten zu richten:
„Wir nehmen unsere Äpfel noch vor dem Michaelis-Markt ab“ hieß
es, oder „Nachbars Ernst ist drei Tage nach dem Vogelschießen
gestorben“. Im Winter wurde nach dem Weihnachtsmarkt gerechnet,
der aber lange vor Weihnachten war. In den engen Gassen standen
die langen Reihen der Buden, wo man alles und jedes haben
konnte, vor allem am Abend, wenn die Lichter wehten und die
vermummten Verkäuferinnen ihre starren Hände über kleinen
Öfchen wärmten; kluge Leute kauften sich da derbe Winterstiefeln,
Pfeffernüsse und einen Kalender oder schon einen
Weihnachtsengel. Dazu kam ein Schnee herunter, wie er ganz
abgekommen ist, und die Bauern stellten ihre Wagen auf große
Kufen, kamen ganz verschneit in die Stadt und hatten dicke Pelze
an, wenn sie Butter und Eier ins Haus brachten, die jetzt für die
Weihnachtsstollen aufgespart wurden.
Aber auch die Menschen sind andere und anders geworden,
fortgezogen, weit weg, oder nur auf den nahen Kirchhof; dort findet
man niemanden, der da nichts verloren hat; nur alte Menschen
gehen noch an ihren Gedenktagen auf den verwachsenen Wegen
und bringen bescheidene Kränze und reden ein weniges mit dem
Wärter des Gartens, der auch schon alt ist, aber alles noch weiß; —
dann vielleicht noch ein paar spielende Kinder in einer Ecke, wo die
verwahrlosten Gräber liegen — ein Ruf, ein Wagenrollen von
draußen, jenseits der Mauern — eine Schwalbe, die zwitschernd
durch die Baumreihen jagt, und die Berge, die von allen Seiten wie
einst herübersehen.
Die Welt unserer Großväter ist versunken; a l l e s trennt uns von
jenen Menschen, deren Leben: arbeiten und feiern, bauen und
wohnen, denken und tun, glauben und hoffen, noch e i n s waren;
aber auch damals war die gesunde, schöne Einheit des Daseins nur
für jene da, die sie fühlten, mit Herz und Auge sahen, wie Ludwig
Richter etwa, und in ihr lebten und sie wahrten.
Als ich vor Jahr und Tag in einer Sommernacht in die kleine Stadt
zurückkam, da fand ich das Haus meiner Mutter wieder; aber die
Fliederbüsche, die über die Mauer hingen, waren abgeschlagen, weil
sie den „Verkehr“ gestört hatten, das Haus war umgebaut und
verwahrlost und von Leuten aller Art bewohnt, die gedankenlos ein-
und ausgingen; und an der Wand des Hauses hing verlumpt der
heilige Weinstock, den keiner mehr ehrt.
Und doch lebt die alte, schöne versunkene deutsche Welt noch
da in ihrer Ganzheit, wo einzig eine Einheit deutschen Lebens und
Daseins in ihrer unfaßbaren Größe und bescheidenen Enge lebt und
leben kann: in uns.
Walter Weichardt
Es ist ein Ros’ entsprungen
Aus einer Wurzel zart
Zum neuen Jahre
Wie heimlicher Weise

Ein Engelein leise
Mit rosigen Füßen
Die Erde betritt,
So nahte der Morgen.
Jauchzt ihm, ihr Frommen,
Ein heilig Willkommen,
Ein heilig Willkommen!
Herz jauchze du mit!
In Ihm sei’s begonnen,

Der Monde und Sonnen
An blauen Gezelten
Des Himmels bewegt.
Du Vater, du rate,
Lenke du und wende!
Herr, dir in die Hände
Sei Anfang und Ende,
Sei alles gelegt!
Mörike
Abschied
O Täler weit, o Höhen,

O schöner, grüner Wald,
Du meiner Lust und Wehen
Andächt’ger Aufenthalt!
Da draußen, stets betrogen,
Saust die geschäft’ge Welt;
Schlag noch einmal die Bogen
Um mich, du grünes Zelt!
Da steht im Wald geschrieben,

Ein stilles, ernstes Wort
Von rechtem Tun und Lieben
Und was des Menschen Hort.
Ich habe treu gelesen
Die Worte, schlicht und wahr,
Und durch mein ganzes Wesen
Ward’s unaussprechlich klar.
Bald werd’ ich dich verlassen,

Fremd in der Fremde gehn,
Auf bunt bewegten Gassen
Des Lebens Schauspiel sehn;
Und mitten in dem Leben
Wird deines Ernsts Gewalt
Mich Einsamen erheben,
So wird mein Herz nicht alt.
Eichendorff
Der frohe Wandersmann
Wem Gott will rechte Gunst erweisen,

Den schickt er in die weite Welt;
Dem will er seine Wunder weisen
In Berg und Wald und Strom und Feld.
Die Trägen, die zu Hause liegen,

Erquicket nicht das Morgenrot,
Sie wissen nur von Kinderwiegen,
Von Sorgen, Last und Not um Brot.
Die Bächlein von den Bergen springen,

Die Lerchen schwirren hoch vor Lust,
Was sollt’ ich nicht mit ihnen singen
Aus voller Kehl’ und frischer Brust?
Den lieben Gott lass’ ich nur walten;

Der Bächlein, Lerchen, Wald und Feld
Und Erd’ und Himmel will erhalten,
Hat auch mein’ Sach’ aufs best’ bestellt!
Eichendorff

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1. Preliminary concept of semisynthesis and its importance 1

3.2.3 Semisynthesis of promising derivatives of rutaecarpine and

4. Semisynthesis of ﬂavones 113

4.1.7 Afzelin A (15) 130

5. Semisynthesis of lignans 181

5.2.1 Semisynthesis of bursehernin and matairesinol dimethyl

6. Semisynthesis of phenolic compounds 209

6.3.10 Semisynthesis of novel derivatives of natural guttiferone-A

7. Semisynthesis of anthocyanins 243

7.4.3 Colorectal cancer 264

8. Semisynthesis of natural products at room temperature 279

9. Semisynthesis of natural products under greener conditions 309

9.3.4 Semisynthesis of novel matrine derivatives 321

10. Semisynthesis of natural products through the insertion of

11. Adaptation of organic reactions in the industrial production

12. New derivatives as nutraceuticals: regulatory considerations 381

13. Computational chemistry of natural product analogues 395

14. Developing semisynthesis methods for neglected tropical

14.2.1 Semisynthesis of p-quinone analog containing

Semisynthesis of Bioactive Compounds and their Biological Activities

synthesis is necessary [12,14]. Semisynthetic derivatives are frequently

a relationship between a compound’s chemical structure and its biological

1.1.2 Why do we need semisynthesis?

regenerative capabilities, this tissue damage is irreversible. Neurodegenera-

mares. At the same time, estrone is synthesized on an industrial scale by

Semisynthesis is the most practical method of obtaining new analogues in

lipopeptides are attractive candidates for further development as new antibi-

1.1.3 Recent advances in the potential applications of

Fig. 1.2 Chemical structures of semisynthetic derivatives with promising biological

1.1.4 Relationship between semisynthesis and drug delivery

Preliminary concept of semisynthesis and its importance

Annonalide Casimirella (icacinaceae) Nine analogs Antitumor [99]

Semisynthesis of Bioactive Compounds and their Biological Activities

properties, by blending, crosslinking, or grafting [124]. Often, natural poly-

enhance their ability to cross biological barriers [136,137]. Various chitosan

[107] J. Alliot, E. Gravel, L. Larquetoux, M. Nicolas, E. Doris, Semisynthesis of macrocar-

[142] A. Geissler, M. Biesalski, T. Heinze, K. Zhang, Formation of nanostructured cellulose

2.1 Current antibiotic resistance mechanism

Semisynthesis of Bioactive Compounds and their Biological Activities

Table 2.1 A classiﬁcation of antimicrobials based on their mode of

Tetracyclines Inhibit protein synthesis

Table 2.2 Types of antimicrobial resistance mechanisms of

Chloramphenicol Drug inactivation

2.2 Chemical derivatization of antibiotics

2.2.1 Semisynthesis of platencin thioether derivatives

in 2021, along with a biological evaluation of these semisynthetic derivatives

Scheme 2.1 Semisynthesis of platencin thioether derivatives.

2.2.2 Semisynthesis of dialkylresorcinol derivatives