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Complementary bibliography XI
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Fundamental bibliography
1. Patrick GL. An Introduction to Medicinal Chemistry. Fifth Edition. Oxford: Oxford University
Press; 2013.
2. Lemke TL, Williams DA, Roche VF, Zito SW (editors). Foye’s Principles of Medicinal Chemistry.
Seventh Edition. Philadelphia: Wolters Kluwer, Lippincott Williams & Wilkins; 2013.
3. Nogrady T, Weaver DF. Medicinal Chemistry. A Molecular and Biochemical Approach. Third Edition.
Oxford: Oxford University Press; 2005.
4. Silverman RB. The Organic Chemistry of Drug Design and Drug Action. Second Edition. Elsevier
Academic Press; 2004.
Complementary bibliography
1. Lednicer D, Mitscher LA. Organic Chemistry of Drug Synthesis. Vols. 1–7. New York: Wiley;
1977–2007.
2. Li JJ, Johnson DS, Sliskovic DR, Roth BD. Contemporary Drug Synthesis. Hoboken, New Jersey: John
Wiley & Sons; 2004.
3. Nicolaou KC, Montagnon T. Molecules That Changed the World. Weinheim: Wiley-VCH; 2008.
4. Corey EJ, Czakó B, Kürti L. Molecules and Medicine. Hoboken, New Jersey: John Wiley & Sons; 2007.
Preface to the second edition
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When preparing this second edition, we have maintained the philosophy of the first
(2018), that is, to emphasize general principles of drug design and drug action from an
organic chemical perspective. The mechanisms of some organic reactions have been
introduced in this edition, to serve as a review and update of processes that may have
been forgotten. The selected examples on drug synthesis are only illustrative of certain general principles that we have tried to rationalize, in the hope that they will
stimulate further study of one of the most brilliant and stimulating activi ties of organic chemistry. We aim to provide a framework of basic drug design/principles into
which current drugs, and more importantly future drugs following on new developments, may be fitted.
The introduction to the principles of drug design is intended for use in undergraduate pharmacy courses in pharmaceutical chemistry (PC) and as an aid in similar
courses in pharmacology and biochemistry where there is a need to appreciate the
rationales behind the design of drugs. Graduates in chemistry just entering the pharmaceutical industry would find that it provides a suitable background for their future work.
There are three fundamental differences in this second edition, compared to the
first one:
1. The most important aspects of each topic of this volume will be indicated at the
end of every chapter and will constitute the skeleton of the topic: Fundamentals.
They are like the branches of a bare Christmas tree to which the leaves and orna-
ments will have to be added.
2. Need for color: Vision is one of the most fundamental means of communication. It
is (or should be) in every scientist’s best intention to make figures and their con-
tent as accurate and easily understandable as possible. One of the most powerful
aspects of images is color, which in turn transforms information into meaning.
Color schemes are often used to place emphasis on particular aspects of a design.
We find that we most often jump straight to the figures and schemes when at-
tempting to understand the critical points of a chapter. Good figure and scheme
design can facilitate study interpretation and can help improve readability.
3. Since PC is dedicated to the study of drug design, synthesis, and analysis, this last
aspect is studied by rapid recognition assays for drugs of abuse, such as morphine,
codeine, heroin, methadone, and amphetamine/methamphetamine in Chapter 6.
We would like to emphasize an aspect that we consider fundamental as instructors:
we aim to simplify the reality of our explanations by giving them a pedagogical characterwitharegularcadence,inwhichstarting from some hypotheses and background, after development in accordance with the scientific method, we arrive at
perfectly clear and concrete conclusions. The inevitable simplification should not lead
to a falsification of PC. Scientific reality is complex, but the pedagogical method at-
https://doi.org/10.1515/9783111316888-203
XIV Preface to the second edition
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tempts to simplify it according to the established and gridded canons. The pursuit of
symmetry in the speech, of the perfect framing, and of the neatness of the reasoning
can lead to deformation of PC.
Scientific phenomena are complex and we try to reduce science to a series of
models. Models are generally seen as “representations of reality”, that is, they translate the modeled entity in a concrete way. From all this it follows that a model is an
approximate and therefore imperfect representation of reality. In this sense, I would
like to refer to the famous painting by the Belgian surrealist painter René Magritte
(November 21, 1898–August 15, 1967) Ceci n’est pas une pipe, which can help understand the relationship between science and the scientific model.
There are many aspects, both of PC and of its fundamental tool, organic chemistry, that are still not known, which makes the student see that, despite their enormous
advances, there is much left to do and it is here, where the young generations have a
lot to say. If we convey the idea that science is not a finished product and therefore
susceptible to being enriched and altered, the student will be able to feel like a protagonist, wanting to “do science” and not just “tell science”, which will encourage in the
students a more critical and more dialectical spirit.
“I cannot teach anybody anything; I can only make them think”
Socrates (470–399 BC)
“Education is the most powerful weapon which you can use to change the world”
Nelson Mandela (1918–2013)
Contents
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Preface to the first edition VII
Preface to the second edition XIII
About the author XXIII
1 Acetylcholine 1
1.1 Goals 1
1.2 Nerve transmission through the synapse 1
1.3 Cholinergic nervous system: muscarinic and nicotinic receptors 2
1.4 Direct agonist drugs 6
1.5 Molecular modifications of ACh 6
1.5.1 Modifications in the ammonium moiety 6
1.5.2 Modifications to the ethylene bridge 8
1.5.3 Modifications in the acyloxy group 9
1.5.3.1 Ester hydrolysis 9
1.5.3.2 Neighboring group participation 9
1.5.3.3 Electronic effects 11
1.6 Synthesis of methacholine and bethanechol 12
1.7 Muscarinic drugs derived from other models 12
1.8 Clinical uses of cholinergic agonists 13
1.8.1 Muscarinic agonists 13
1.8.2 Nicotinic agonists 13
1.9 Muscarinic antagonists: clinical effects 13
1.9.1 Clinical uses 14
1.10 Muscarinic antagonists 14
1.10.1 Atropine 14
1.10.2 Hyoscine 15
1.11 Structural analogs based on atropine 16
1.12 Anticholinergic drugs obtained by synthesis: structure–activity
relationships 16
1.13 M2 antimuscarinic drugs 17
1.14 Disconnection and syntheses of aminoalkyl esters 18
1.14.1 Simple alcohol disconnections 20
1.14.1.1 Cyclopentolate 20
1.14.2 Aminoesters 21
1.14.3 Aminopropanols 21
1.15 Amidoammonium drugs 22
1.16 Antagonist drugs on nicotinic receptors 23
1.16.1 Decamethonium and suxamethonium 25
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1.16.2 Atracurium 26
1.17 Anticholinesterases and acetylcholinesterase 27
1.17.1 Effect of anticholinesterases 27
1.17.2 Acetylcholinesterase active center 28
1.17.2.1 Binding interactions at the active site 28
1.17.2.2 The mechanism of hydrolysis 29
1.17.3 Anticholinesterase drugs 29
1.17.3.1 Carbamates 29
1.17.3.2 Organophosphorus compounds 33
1.18 Fundamentals 36
2 Noradrenaline (norepinephrine) 37
2.1 Goals 37
2.2 Introduction 37
2.3 Adrenergic synapses 37
2.4 Drugs that focus on noradrenaline biosynthesis: false
transmitters 38
2.5 Drugs that affect the release of stored noradrenaline 39
2.6 Mechanism of action of MAO 42
2.7 Adrenergic indirect drugs 43
2.8 Catechol-O-methyltransferase inhibitors (COMT) 46
2.9 Direct adrenergic drugs (postsynaptic agonists) 46
2.9.1 Selectivity for α-adrenoreceptors versus β 48
2.9.1.1 Substitution of the N-alkyl group 48
2.10 Adrenergic β-blockers 53
2.10.1 Regioselective opening of epoxides in basic media 55
2.10.2 Regioselective opening of epoxides in acidic media 56
2.11 α-Adrenergic blockers 59
2.11.1 Competitive antagonists of NA and adrenaline 59
2.11.2 Noncompetitive antagonists of NA, especially β-haloethylamines,
capable of irreversibly alkylating the receptor 60
2.11.3 Benzodioxanes and other synthetic heterocycles: imidazolines 60
2.12 Fundamentals 62
3 Dopamine 63
3.1 Goals 63
3.2 Introduction: antiparkinsonians related to the action or release of
3.2.1 Conformationally restricted dopamine congeners 64
3.3 Direct agonists 65
3.4 MAO and COMT inhibitors 66
dopamine 63
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3.5 Drugs capable of causing the release of dopamine from the
peripheral neural sites at the presynaptic level 67
3.6 Other dopaminergic agonists 69
3.7 Dopaminergic antagonists 70
3.7.1 Tricyclic neuroleptics: phenothiazines and thioxanthenes 70
3.7.1.1 Synthesis of the tricyclic system 71
3.7.1.2 Pharmacophore of tricyclic neuroleptics 75
3.7.2 Butyrophenones and analogs 77
3.7.2.1 Mannich reaction 77
3.7.3 Ortho-Methoxybenzamides (orthopramides) 81
3.8 Fundamentals 82
4 Serotonin and reuptake inhibitors of biogenic amines 83
4.1 Goals 83
4.2 Introduction 83
4.3 Reuptake inhibitors: tricyclic antidepressants 83
4.4 MAO inhibitors (MAOIs) 85
4.5 Serotonin 86
4.6 Selective serotonin reuptake inhibitors (SSRIs) 88
4.7 Direct action on serotonergic receptors 88
4.7.1 5-HT
agonists: antimigraine drugs 88
1D
4.7.1.1 Sumatriptan and other triptans 89
4.7.2 5-HT
4.7.3 5-HT
agonists 92
1A
antagonists 93
3
4.8 Summary 95
4.9 Fundamentals 96
5 Amino acid neurotransmitters 97
5.1 Goals 97
5.2 Introduction 97
5.3 Inhibitors of γ-aminobutyric acid (GABA) 97
5.4 Presynaptic modulators 98
5.5 Enzyme inhibitors that have pyridoxal phosphate as cofactor 99
5.6 Postsynaptic modulators 102
5.6.1 Benzodiazepines 103
5.6.1.1 Mechanism of the rearrangement reaction to
1,4-benzodiazepines 105
5.6.1.2 Mechanism of metabolic hydrolysis of chlordiazepoxide (Librium
1960) 105
5.6.1.3 Second-generation benzodiazepines [diazepam (Valium
5.6.1.4 Structure–activity relationships 106
5.6.2 Fixation of steroids to GABA
®
,
®
)] 106
109
A
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5.6.3 Other drugs related to benzodiazepines 110
5.6.4 Barbituric acids (or barbiturates) 110
5.7 Fundamentals 114
6 Peptides as neurotransmitters: narcotic analgesics 115
6.1 Goals 115
6.2 Morphine 115
6.2.1 Structure–activity relationships of morphine 116
6.2.1.1 The phenolic group 116
6.2.1.2 Alcohol at position 6 116
6.2.1.3 The 7–8 double bond 117
6.2.1.4 The N-methyl group 118
6.2.1.5 E ring and the ethereal bridge 118
6.2.1.6 Stereochemistry 118
6.2.2 Development of morphine analogs: strategies 120
6.2.2.1 Extension of the drug: addition of “extra” binding groups 120
6.2.2.2 Simplification or dissection of the drug 123
6.2.2.3 Increased rigidity 129
6.2.3 Multiple analgesic receptors 131
6.2.3.1 Mu receptor (μ) 131
6.2.3.2 Kappa receptor (κ) 132
6.2.3.3 Delta receptor (δ) 132
6.2.4 Pain scale 133
6.2.5 Agonists and antagonists 133
6.2.6 Enkephalins and endorphins 135
6.2.7 Enkephalin analogs 136
6.3 Preliminary colorimetric methods to detect drugs of abuse by police
forces 136
6.3.1 Identification of morphine 137
6.3.2 Identification of morphine, codeine, and heroin 137
6.3.3 Identification of methadone 138
6.3.4 Identification of amphetamine/methamphetamine 138
6.3.5 Identification of cocaine 138
6.4 Fundamentals 140
7 Histamine and antihistamines 141
7.1 Goals 141
7.2 Histamine 141
7.2.1 H1-antihistamines: synthesis and SARs 143
7.2.2 Second-generation H1-antihistamine drugs 148
7.3 Cimetidine: example of a rational approach in the design of a
drug 151
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7.3.1 Beginnings: ulcer therapy in 1964 151
7.3.2 Two histamine receptors 152
7.3.3 Looking for a leader: histamine 153
α
7.4 Searching for a leader: N
-guanylhistamine 154
7.5 The theory of chelation 158
7.6 From a partial agonist to an antagonist: development of
burimamide 158
7.7 Development of methiamide 159
7.8 Cimetidine development 162
7.8.1 Cimetidine metabolism 165
7.8.2 Bredereck reaction 165
7.8.2.1 Cimetidine synthesis 165
7.8.3 Conformational isomers of cimetidine 166
7.8.4 Desolvation 168
7.8.5 Development of the 2-nitroethene-1,1-diamine group 170
7.9 Variation of the imidazole ring and the cyanoguanidine moiety of
cimetidine: ranitidine 172
7.10 Summary of cimetidine design 173
7.11 Comparison between H1 and H2 antagonists 173
7.12 Fundamentals 174
8 Enzymatic inhibitors I 175
8.1 Goals 175
8.2 Introduction 175
8.3 Carbonic anhydrase (CA) inhibitors 175
8.4 Renin–angiotensin pathway 178
8.4.1 Angiotensin II antagonists: X-ray crystallographic studies 179
8.5 Fundamentals 184
9 Enzymatic inhibitors II 185
9.1 Goals 185
9.2 Introduction 185
9.3 Classification of nonsteroidal anti-inflammatory drugs (NSAIDs) 189
9.3.1 Arylacetic acids or “fenacs” 189
9.3.1.1 Blanc chloromethylation or Blanc reaction 189
9.3.1.2 Reduction of Wolff–Kishner 193
9.3.2 Arylpropionic acids or “profens” 194
9.3.3 Naproxen 194
9.3.4 N-Arylanthranilic (fenamic) acids 195
9.3.5 Enols (oxicams) 196
9.3.6 COX-2 selective inhibitors: coxibs 197
9.4 Fundamentals 199
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10 Design of drugs acting on transport through biological
membranes 200
10.1 Goals 200
10.2 Design of drugs that act on transport through cell membranes 200
10.3 Voltage-gated sodium channels 200
10.3.1 Local anesthetics 203
10.3.1.1 Structure–activity relationships in local anesthetics 204
10.3.1.2 Physicochemical properties and mode of action 206
10.4 Voltage-dependent calcium channels 206
10.4.1 Calcium channel blockers: structural families 207
10.4.1.1 1,4-Dihydropyridines 207
+
10.4.1.2 Agents that act as activators of K
+/K+
10.4.2 H
-ATPase inhibitors: antiulcer drugs 210
208
10.5 Fundamentals 211
11 Enzymatic inhibition: inhibitors of the biosynthesis of the cellular
wall 212
11.1 Goals 212
11.2 Antibiotics 212
11.3 Penicillins 212
11.3.1 Structure of penicillins 213
11.3.2 Various penicillins 213
11.3.3 Properties of penicillin G 214
11.3.4 Structure–activity relationships of penicillins 215
11.3.5 Sensitivity of penicillin G to acids 215
11.3.5.1 Ring strain 215
11.3.5.2 The highly reactive carbonyl group of the β-lactam system 215
11.3.5.3 Influence of the acylic lateral chain (neighboring-group
participation) 216
11.3.5.4 Facing the problem of acid sensitivity 216
11.3.6 Penicillins sensitive to β-lactamases 216
11.3.7 Facing the problem of β-lactamase sensitivity 218
11.3.8 Resistance to penicillins 220
11.3.8.1 Permeability barrier 221
11.3.8.2 High levels of the enzyme transpeptidase 222
11.3.8.3 Presence of β-lactamases 222
11.3.9 Addressing the narrow-spectrum problem 222
11.4 Cephalosporins 225
11.4.1 SARs of cephalosporin C 228
11.4.2 Cephalosporin C analogs by variation of the 7-acylamine side
chain 228
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11.4.3 Cephalosporin C analogs by variation of the 3-acetoxymethyl side
chain 230
11.4.4 Synthesis of 3-methylated cephalosporins 231
11.4.5 Disclaimer 231
11.4.6 Summary of the properties of cephalosporins 231
11.5 Clavulanic acid (Beechams, 1976) 232
11.6 Mechanism of action of penicillins and cephalosporins 233
11.7 Fundamentals 238
12 Enzymatic inhibition: other antibacterial agents 239
12.1 Goals 239
12.2 Introduction 239
12.3 SARs 239
12.4 Sulfanilamide analogs 240
12.5 Applications of sulfonamides 241
12.6 Mechanism of action 242
12.7 Synthesis of sulfonamides 244
12.8 Examples of other antimetabolites 245
12.8.1 Trimethoprim 246
12.9 Antibacterial agents affecting protein synthesis 246
12.9.1 Rifamycins 246
12.9.2 Aminoglycosides 247
12.9.3 Tetracyclines 247
12.9.4 Chloramphenicol 248
12.9.4.1 Aldol reaction 248
12.9.4.2 Nitro-aldol reaction or the Henry reaction 249
12.9.5 Erythromycin 250
12.9.6 Aminoacridines 250
12.9.7 1,8-Naphthyridine and fluoroquinolones 253
12.9.7.1 Orthoester 254
12.9.7.2 Synthesis of diethyl ethoxymethylenemalonate, intermediate for the
preparation of norfloxacin and nalidixic acid 255
12.10 Why 4-quinolone-3-carboxylic acids do not decarboxylate despite
being β-ketoacids? 257
12.11 Fundamentals 258
13 Enzymatic inhibition: inhibitors of biosynthesis of nitrogenous
bases 259
13.1 Goals 259
13.2 Introduction 259
13.3 Nucleic acids 259
13.4 The birth of cancer chemotherapy: accident and research 259
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