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Joaquín M. Campos Rosa
Drug Design and Action
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Joaquín M. Campos Rosa
Pharmaceutical
Chemistry
Volume 1: Drug Design and Action
2nd Edition
Author
Prof. Joaquín M. Campos Rosa
Department of Pharmaceutical and Organic Chemistry
University of Granada
Campus de Cartuja
18071 Granada
Spain
jmcampos@ugr.es
ISBN 978-3-11-131654-3
e-ISBN (PDF) 978-3-11-131690-1
e-ISBN (EPUB) 978-3-11-131721-2
Library of Congress Control Number: 2023946629
Bibliographic information published by the Deutsche Nationalbibliothek
The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie;
detailed bibliographic data are available on the internet at http://dnb.dnb.de.
© 2024 Walter de Gruyter GmbH, Berlin/Boston
Cover image: alice-photo/iStock/Getty Images Plus
Typesetting: Integra Software Services Pvt. Ltd.
Printing and binding: CPI books GmbH, Leck
www.degruyter.com
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“The expert in anything was once a beginner”
Anonymous
“What we learn with pleasure we never forget”
Alfred Mercier (1816–1894)
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Preface to the first edition
Global objectives of pharmaceutical chemistry
1. To understand the interrelation between structure, physicochemical properties,
pharmacological activity, and therapeutic utility
2. To know the methods and strategies used in the generation of drugs
3. To know the interactions between drugs and their biological targets
4. To know and propose the structural modifications that affect the properties of
the drugs
5. To know the general methods and the synthetic strategies for the preparation of
drugs
6. To know the analytical and spectroscopic methods applicable to the structural
identification and elucidation of drugs, and related compounds
7. To be able to name and formulate a drug in acco rdance with th e systematic
IUPAC nomenclature
8. To know and become able to predict the transformation of drugs in the body
9. To know and be able to estimate the risks associated with the use of reagents,
solvents and the development of processes in the chemical laboratory
10. To know how to acquire and use information related to drugs
The objective of pharmaceutical chemistry (hereinafter PC) is the chemical study of
drugs and the active ingredients of drugs in order to de termine the relationship be-
tween chemical structure, physicochemical properties, reactivity, and biological re-
sponse, with the ultimate aim of providing the knowledge necessary for the creation
of new drugs. Since most of the drugs are organic in nature, PC is mainly based on the
knowledge of organic chemistry, although it requires a strong familiarity with and a
solid base in biochemistry. It is also nourished by other sciences such as (a) pharma-
cognosy, which studies natural products as a source of new active principles; (b) phar-
macology, which allows the establishment of experimental models for the evaluation
of new active principles; and (c) molecular pharmacology. The latter tries to explain
the biological effects at the molecular level , interpreting the phenomena related to
the association between a drug and the biomolecules that trigger its action, all from
the point of view of structural and physicochemical properties.
Although drug design in its origins focusedprimarilyonthesimplechemical
modifications of naturally occurring molecules, current design trends are based on
the study of drug interactions with their targets at the molecular level. The develop-
ment of molecular biology and genetic engineering over the last decade has allowed
the detailed study of many targets in the action of drugs, such as enzymes, membrane
receptors, and nucleic acids. Therefore, part of the design of new drugs is currently
based on drug–receptor interactions.
https://doi.org/10.1515/9783111316901-202
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The complete work consists of the following two volumes:
Pharmaceutical Chemistry
Volume 1: Drug Design and Action
Pharmaceutical Chemistry
Volume 2: Drugs and Their Biological Targets
After the first part, in which general principles are explained, in the second volume,
the knowledge acquired for the establishment of the therapeutic arsenal according to
the different molecular objectives is applied. There are excellent treatises of PC or me-
dicinal chemistry, but require the reader to have a solid foundation. Our book is
aimed at pharmacy and chemistry students who intend to enter the exciting world of
drug development. Therefore, we have not tried to cover this study in an exhaustive
way, but rather to establish the bases that in a first stage allow the fostering of inter-
est in this scientific field. This is our humble goal, and if we achieve it, we will fee l
satisfied that we have fully achieved our objective. We have tried to achieve a balance
between chemical and biological aspects, highlighting the strong multidisciplinary
character of this science. As far as possible, the number of drugs of both volumes has
been reduced to a minimum, sufficient to understand the philosophy of PC and with-
out overburdening the beginner with more and more examples, and therefore we
hope to avoid a “can’t see the wood for the trees”.
Drug synthesis is approached from a double point of view in Chapter 8 of this
first volume:
(a) The retrosynthetic analysis that allows the bond breaking of the molecule to ar-
rive at a structurally simpler starting material and that will allow us to carry out
the direct and real process of synthesis in a rational way.
(b) The ability to propose the corresponding synthesis, based on the information ob-
tained in the retrosyn thetic analysis, mechanism of reactions, and reactivity of
organic compounds. The basis of biology is chemi stry, which permits the crea-
tion of drugs (chemists acting as molecular architects), as well as the analysis of
the interactions between the drug and its biological objective, which will permit
the design of more active structures after their optimization. This first volume
provides exercises and their solutions, allowing the reader to assess to what de-
gree he or she has understood
The work shown here is the result of extensive teaching experience at the Faculty of
Pharmacy of Granada Universit y. We want to thank the role of the students in the
noble task of teaching. They give meaning to our work and stimulate us to keep both
knowledge and methodology up to date. We want to thank our parents, partners, and
children for the support we have received. They have demonstrated that constancy is
VIII Preface to the first edition
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fundamental to achieving our objectives, while we have neglected our families during
the time devoted to this work.
It is the explicit desire of the authors to receive any suggestions, additions and cor-
rections, which will surely make possible an expansion of the contents of the work.
Fundamental bibliography
Victoria F. Roche, S. William Zito, Thomas L. Lemke, David A. Williams. Foye’s Principles of Medicinal
Chemistry. Wolters Kluwer Heath, 8th Edition, 2019.
Thomas Nogrady, Donald F. Weaver. Medicinal Chemistry. A Biochemical Approach. Editorial Oxford
University Press, 3rd Edition, 2005.
Patrick, Graham L. An Introduction to Medicinal Chemistry. Editorial Oxford University Press, 5th
Edition, 2013.
Enrique Raviña. The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. Wiley-VCH,
Verlag GmbH & Co., KGaA, 1st Edition, 2011.
Richard B. Silverman, Mark W. Holladay. The Organic Chemistry of Drug Design and Drug Action. Elsevier
Academic Press, 3rd Edition, 2015.
Camille Georges Wermuth, David Aldous, Pierre Raboisson, Didier Rognan. The Practice of Medicinal
Chemistry. Academic Press, 4th Edition, 2015.
Corwin Hansch, Albert Leo. Exploring QSAR: Fundamentals and Applications in Chemistry and Biology.
American Chemical Society, Washington, DC, 1995.
Hugo Kubinyi. QSAR: Hansch Analysis and Related Approaches, VCH Verlagesellschaft mbH, 1993.
Complementary bibliography
Daniel Lednicer. Organic Chemistry of Drug Synthesis. Vols. 1–6, Wiley-Interscience, 1977–1998.
Stuart Warren, Paul Wyatt. Organic Synthesis: The Disconnection Approach. Wiley, 2nd Edition, 2008.
Complementary bibliography IX
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Preface to the second edition
The objective of pharmaceutical chemistry (PC) is the chemical study of drugs, the ac-
tive ingredients of medicines, in order to determine the relationship between chemi-
cal structure, physicochemical properties, reactivity, and biological response, with the
ultimate aim of providing the necessary knowledge for the creation of new drugs.
Since most drugs are organic in nature, therapeutic chemistry or PC is mainly
based on the knowledge of organic chemistry, although it requires a strong biological
connection with a solid foundation in biochemistry. On the other hand, it also draws
on other subjects such as,
a) Pharmacognosy, which studies natural products as a source of new active
ingredients.
b) Pharmacology, which allows the establishment of experimental models for the
evaluation of new active ingredients.
c) Molecular pharmacology, which tries to explain biological effects at the molecu-
lar level, interpreting the phenomena related to the association between a drug
and the biomolecules that trigger its action, all from the point of view of struc-
tural and physicochemical properties.
Although drug design, the ultimate objective of PC, was originally focused on simple
chemical modifications of molecules of natural origin, current design trends are
based on the study of drug interactions with their target structures at the molecular
level. The development experienced in the last decade by molecular biology and ge-
netic engineering has allowed the detailed study of many target molecules in drug ac-
tion, such as enzymes, membrane receptors and nucleic acids. Therefore, part of the
design of new drugs is currently based on drug–receptor interactions.
The synthesis of the designed compounds is another aspect to be considered in
the study of PC.
Organic chemistry is approached from a mechanistic viewpoint. The ability to
write feasible reaction mechanisms in organic chemistry depends on the extent of the
individual’s preparation. These two volumes assume the knowledge obtained in a
two-semester undergraduate course of organic chemistry. I am going to re view how
to draw Lewis structures and how to ca lculate formal charges. In order to write or
understand reaction mechanisms, it is essential to be able to construct Lewis struc-
tures for any organic compound. The electron flow pathway has become the building
blocks of the mechanistic processes. I am going to use the concept of electron flow
with the rigorous use of curved arrows as an electron bookkeeping device.
I have attempted to keep the use of IUPAC names of organic compounds to a bare
minimum to enhance the readability of the text. In the discussion of reactions, I drew
out the structures rather than the names of the compounds.
I will try to condense the essentials of PC in a student-friendly manageable way. I
will do this by concentrating purely on the basics of the subject without going into
https://doi.org/10.1515/9783111316901-203
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