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Joaquín M. Campos Rosa
Pharmaceutical Chemistry
Also of interest
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ISBN ----, e-ISBN ----

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Joaquín M. Campos Rosa

Pharmaceutical
Chemistry

Volume 2: Drugs and Their Biological Targets

2nd Edition
Author
Prof. Joaquín M. Campos Rosa
Department of Pharmaceutical
and Organic Chemistry
University of Granada
Campus de Cartuja
18071 Granada
Spain
[email protected]

ISBN 978-3-11-131655-0
e-ISBN (PDF) 978-3-11-131688-8
e-ISBN (EPUB) 978-3-11-131724-3

Library of Congress Control Number: 2024930597

Bibliographic information published by the Deutsche Nationalbibliothek

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© 2024 Walter de Gruyter GmbH, Berlin/Boston

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Printing and binding: CPI books GmbH, Leck

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“I’ve been a fortunate man in life. Nothing has come easily”
Sigmund Freud (1856–1939)

“Simplicity is the ultimate sophistication”

Leonardo da Vinci (1452–1519)
Preface to the first edition
Pharmaceutical chemistry

In recent years, there have been enormous advances in the fields of biochemistry and
molecular biology, organic synthesis, techniques of separation, and instrumental anal-
ysis, especially HPLC, NMR, MS, and X-ray crystallography. Moreover, the spectacular
development of information technology and robotics has greatly contributed to
changes in the approach to the development of new drugs by the pharmaceutical in-
dustry and centers dedicated to research in this field. This suggests that the drugs of
the future will probably not resemble those used in the past, but what is absolutely
certain is that they will have been developed on a more solid basis of knowledge, that
is, based less and less on serendipity and more on the biochemical disorders produced
by the disease, on the rational design of prototypes, and on biotechnology.
This volume is divided into 13 chapters, conveying a systematic study of different
drugs, based on the systems they act upon. The drugs will be discussed as a function
of the interference that they cause in ionic transport, changes of permeability or alter-
ations of the membrane structure, and those whose mechanism is a consequence of
its binding to a membrane or intracellular receptors, which motivates a signal trans-
duction through second messengers. In addition, these chapters will study the chemi-
cal synthesis of structures used as prototypes of the different drug families, as well as
those drugs of great therapeutic and/or chemical interest.
We will begin with the study of classical neurotransmitters such as acetylcholine
and noradrenaline. The chemical transmitter found in all ganglia, neuromuscular
junctions, and postganglionic terminations of the parasympathetic nervous system is
acetylcholine, whereas noradrenaline is only found in postganglionic sympathetic ter-
minations. The study of acetylcholine is addressed in Chapter 1, which describes the
effects of agonist drugs on muscarinic receptors and of antagonistic drugs on the mus-
carinic and nicotinic receptors, respectively. An attempt is made to explain the musca-
rinic response with the study of cholinergic or parasympathetic-mimic agonists. A
distinction is made between direct and indirect agonists, as well as acetylcholinester-
ase inhibitors, which can be used as pesticides, and have great military and economic
implications.
The nicotinic receptor, which regulates the nonselective channel of certain cati-
ons (Na+, K+, and Ca2+), thereby allowing a depolarization during nerve transmission,
is described. There follows a brief study of the agonists, which have no therapeutic
relevance, to describe their antagonistic activities as blockers of the neuromuscular
junction. The chapter concludes with a description of the antimuscarinic agents, with
the natural tropane structure and the synthetic derivatives, with mydriatic, spasmo-
lytic, and antiulcer utilities.
We then study the adrenergic system, to which Chapter 2 is devoted. In it, we
study the different stages of the neurotransmitter cycle (biosynthesis, storage, release,

https://doi.org/10.1515/9783111316888-202
VIII Preface to the first edition

association with presynaptic receptors that regulate biosynthesis and release, reup-
take, and metabolism). Drugs that may act at nonreceptor levels such as false neuro-
transmitters, adrenergic blockers, enzyme inhibitors, reuptake inhibitors, and indirect
adrenergic agonists such as Ephedra alkaloids, amphetamines, and related compounds
are described. This is followed by the study of adrenergic drugs at the receptor level,
establishing the division of receptors suggested by Ahlquist and describing the differ-
ent physiological responses. A profound analysis is made of both agonists and antago-
nists, marking the structural aspects that give receptor selectivity and stereospecificity,
with great therapeutic applications, such as bronchodilators, antihypertensives, and
nasal decongestants.
The study of dopamine is discussed in Chapter 3, where the central (D1 and D2)
and peripheral receptors are described; the different neurotransmitter conformers
are discussed, and agonists, especially antiparkinsonian agents, and the antagonists
such as neuroleptic drugs. Phenothiazine derivatives and other tricyclic systems, bu-
tyrophenones and their derivatives, benzamides, and derivatives of ergot alkaloids
are also discussed. A study of drugs with antiparkinsonian action, whose mechanism
is to modulate the biosynthesis, release, and metabolism of dopamine, is also car-
ried out.
Chapter 4 deals with serotonin, or 5-hydroxytryptamine (5-HT), and its receptors,
describing a series of antidepressant drugs whose mechanism of action is to inhibit
the reuptake, or the metabolism, of serotonin. It also addresses a study of agonists
and antagonists that are widely dispersed structurally, and sometimes also linked to
dopaminergic receptors, which have pharmacological application, such as anxiolytic,
antidepressant, anorexic, antimigraine, and antiemetic medications. Lysergic acid de-
rivatives and other ergoline compounds, whose structural features are linked to D2
and 5-HT1D antagonists, are also studied. Among the 5-HT2 and 5-HT3 antagonists, the
indole derivatives (of the ondansetron type), widely used as antiemetics in patients
undergoing radiotherapy treatment, are very useful.
In Chapter 5, the inhibitory amino acids (neutral amino acids: GABA, glycine, and
taurine) and excitatory amino acids (glutamic and aspartic acids) of the central ner-
vous system are introduced. When studying the GABA receptor as a regulator of the
chloride ion channel, the structure–activity relationships of benzodiazepines are ana-
lyzed because of their importance as anxiolytic drugs.
Chapter 6 is devoted to the study of narcotic analgesics, developing the concept of
endogenous agonists (enkephalins and endorphins) and the types of opioid receptors
(μ, δ, κ, and σ). After a description of the opium alkaloids used as narcotic analgesics
and antitussives, we deal with the stereochemical aspects of morphine and derivatives
that preserve the pentacyclic system, with agonist and antagonistic activities. Next,
semisynthetic derivatives are produced by the technique of structural disjunctive vari-
ation, indicating their structure–activity relationships. Finally, the structure–activity
relationships are established with the endogenous peptides.
 Pharmaceutical chemistry IX

Chapter 7 begins with the study of histamine. It is a widely distributed chemical

messenger, which plays an important role in certain intracellular communication pro-
cesses. The chapter describes the biological cycle of histamine and addresses its struc-
tural aspects. The different receptors and more importantly, from a pharmacological
point of view, the different H1 and H2 antagonists are also described. They begin with
the processes of structural variation made to improve the action and avoid side ef-
fects such as sedation. The second part of the chapter deals with the systematic study
of a classic example of rational development of a drug such as cimetidine.
Many clinically useful agents act by inhibiting the organism’s own enzymes in-
volved in the biosynthesis or metabolic degradation of endogenous substances that
perform important functions. In Chapter 8, we will discuss some examples of drugs
useful in therapeutics, including carbonic anhydrase inhibitors. In the second part of
this chapter, starting with the renin–angiotensin system and the importance of the
inhibition of the angiotensin-converting enzyme for the design of antihypertensive
drugs, the focus will be on the study of the peptide mediators. It describes how from
teprotide, a nonapeptide found in the venom of the viper Bothrops jararaca, and tak-
ing as a model the zinc-containing metalloprotease (carboxypeptidase A), captopril
was reached and then extended to two large families: carboxyalkanoyl and mercap-
toalkanoyl amino acids.
Chapter 9 describes the different metabolites of arachidonic acid and then pro-
ceeds to the development of prostaglandins and analogs with therapeutic utility. An-
tagonists of the cyclooxygenase enzyme of great therapeutic utility, such as analgesic
drugs (which increase sensitivity to pain or reduce the pain threshold), antipyretics,
and nonsteroidal anti-inflammatory drugs are also described. Next, the different pro-
totypes (derivatives of salicylic acid, p-aminophenol, N-arylanthranilic, arylacetic, or
propionic acids, etc.) used as antianxiety and antipyretic drugs are described. Finally,
the selectivity of action on the isoenzyme cyclooxygenase-2 as a source of anti-
inflammatory drugs with a lower incidence of side effects is discussed.
In Chapter 10, some families of drugs will be considered whose mode of action
consists in the modulation of certain ion channels that, unlike those considered until
now, are not regulated by specific ligands but by potential differences: the arrival of a
nerve impulse (change in membrane potential) is able to regulate the opening or clos-
ing of an ion channel. These channels, known as potential-dependent channels, gener-
ally result in faster changes in the membrane potential than those caused by the
activation of the ion channels dependent on a ligand. Local anesthetics are com-
pounds that decrease the excitability of cells by blocking the potential-dependent so-
dium channels. From a therapeutic point of view, the design of calcium channel
blockers has become important because these blockers treat a variety of conditions
and are useful as antiarrhythmics for the regulation of the rhythm of cardiac contrac-
tion. Moreover, they are also useful as hypotensors (antihypertensive drugs), for their
ability to relax the heart muscle and the smooth fiber of blood vessels, and as antian-
ginals, for their ability to counteract the coronary ischemia associated with angina
X Preface to the first edition

pectoris. Although the role of potassium channels in the transmission of membrane

potential and in cellular excitability processes has long been known, the design of se-
lective drugs at this level is a relatively unexplored field, partly due to the scarcity of
ligands that may allow the study of the electrophysiology of the channels. The chapter
concludes with the study of inhibitors of ATPase H+/K+ as antiulcer drugs, among
which omeprazole stands out.
Penicillins and cephalosporins are studied in Chapter 11. The development of pen-
icillins is responsible for the dramatic increase in the life expectancy of the popula-
tion in western countries, which previously remained below the age of 50. Many
scientists consider penicillins as the most important achievement of medicine in the
last century. Since the commercialization of cephalothin in 1962, cephalosporins have
risen to a position of distinction in the world of antibiotics. The modification of side
chains to the cephalosporin nucleus has produced an extraordinary proliferation of
new compounds for clinical use, which have become very important in the treatment
of bacterial infections due to their relatively low toxicity, broad antibacterial spec-
trum, bactericidal activity, and activity against β-lactamases.
Chapter 12 presents the therapeutic antibacterial arsenal belonging to other fields
and their mechanisms of action, such as sulfonamides, agents affecting protein synthesis,
aminoglycosides, tetracyclines, chloramphenicol, aminoacridines, and fluoroquinolones.
Aminoglycosides, tetracyclines, chloramphenicol, and macrolides interfere with the syn-
thesis of proteins at the ribosome level. Sulfamides and trimethoprim act as antimetabo-
lites, preventing the synthesis of purines. Fluoroquinolones act at the level of DNA
strands, preventing supercoiling by inhibition of a topoisomerase such as DNA gyrase.
In Chapter 13, we will study anticancer and antiviral drugs. More than 100 che-
motherapy drugs are currently being used in cancer treatment, either alone or in
combination with other medications or treatments. From antimetabolites, we will
study 5-fluorouracil and one of its prodrugs, capecitabine, while from the mitosis
inhibitors, paclitaxel and docetaxel will be the objects of our study. From the most
modern drugs, we will cover tyrosine kinase inhibitors such as gefitinib.
Advances in the chemotherapy of viral diseases are much fewer than those
achieved in the treatment of bacterial infections. In the USA, only a few antiviral
agents of demonstrated clinical value are available. However, we will address some
examples of extensive medical treatment.
The final version of this work is the responsibility of the authors. We apologize to
the readers for any errors and omissions that may exist in advance, and we look for-
ward to your generous help to overcome them in the future.
 Complementary bibliography XI

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
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 cer-
tain 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 activities of or-
ganic chemistry. We aim to provide a framework of basic drug design/principles into
which current drugs, and more importantly future drugs following on new develop-
ments, may be fitted.
The introduction to the principles of drug design is intended for use in under-
graduate 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 phar-
maceutical industry would find that it provides a suitable background for their fu-
ture 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 char-
acter with a regular cadence, in which starting from some hypotheses and back-
ground, 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

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 trans-
late 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 under-
stand the relationship between science and the scientific model.
There are many aspects, both of PC and of its fundamental tool, organic chemis-
try, 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 protag-
onist, 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
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
XVI Contents

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
dopamine 63
3.2.1 Conformationally restricted dopamine congeners 64
3.3 Direct agonists 65
3.4 MAO and COMT inhibitors 66
 Contents XVII

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-HT1D agonists: antimigraine drugs 88
4.7.1.1 Sumatriptan and other triptans 89
4.7.2 5-HT1A agonists 92
4.7.3 5-HT3 antagonists 93
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®)] 106
5.6.1.4 Structure–activity relationships 106
5.6.2 Fixation of steroids to GABAA 109
XVIII Contents

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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