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Basic Concepts in Medicinal Chemistry Second Edition Marc

W. Harrold

Basic Illustrated Medicinal Plants Basic Illustrated

Series Meuninck

Out of the Blue M M Harrold

Media, Culture and Society: An Introduction 2nd Edition

Paul Hodkinson
Inclusive Education in Low Income Countries A Resource
Book for Teacher Educators Parent Trainers and Community
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Talking to My Daughter About the Economy or How Capitalism

Works and How It Fails Yanis Varoufakis

Heidegger on Logic 1st Edition Filippo Casati

Remember Courage Healing Hearts Book 6 Ginny Sterling

The Meteorology of Posidonius Issues in Ancient Philosophy

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American Dreamer. 1st Edition Adriana Herrera.
BASIC CONCEPTS IN
MEDICINAL CHEMISTRY
BASIC CONCEPTS IN
MEDICINAL CHEMISTRY
3rd Edition

MARC W. HARROLD, BS Pharm, PhD

Professor of Medicinal Chemistry
Duquesne University
School of Pharmacy
Pittsburgh, Pennsylvania

ROBIN M. ZAVOD, PhD, FAPhA

Editor-in-Chief, Currents in Pharmacy Teaching and Learning
Professor of Pharmaceutical Sciences
Midwestern University College of Pharmacy
Downers Grove, Illinois
Any correspondence regarding this publication should be sent to the publisher, American Society of Health-
System Pharmacists, 4500 East-West Highway, suite 900, Bethesda, MD 20814, attention: Special Publishing.

The information presented herein reflects the opinions of the contributors and advisors. It should not be inter-
preted as an official policy of ASHP or as an endorsement of any product.

Because of ongoing research and improvements in technology, the information and its applications contained
in this text are constantly evolving and are subject to the professional judgment and interpretation of the
practitioner due to the uniqueness of a clinical situation. The editors and ASHP have made reasonable efforts
to ensure the accuracy and appropriateness of the information presented in this document. However, any user
of this information is advised that the editors and ASHP are not responsible for the continued currency of the
information, for any errors or omissions, and/or for any consequences arising from the use of the information
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Library of Congress Cataloging-in-Publication Data

Names: Harrold, Marc W., author. | Zavod, Robin M., author. | American Society of Health-System Pharmacists,
issuing body.
Title: Basic concepts in medicinal chemistry / Marc W. Harrold, Robin M. Zavod.
Description: 3rd edition. | Bethesda, MD : ASHP, [2023] | Includes bibliographical references and index. |
Summary: “This text will focus upon the basic, fundamental concepts that govern the discipline of medicinal
chemistry as well as how and why these concepts are essential to therapeutic decisions. The text will include
numerous examples of each concept as well as review questions designed to help readers assess their
understanding of these concepts. Each chapter will also include a section that focuses upon the application
of the pertinent concepts to therapeutic decisions. The text is meant to be comprehensive in regards to the
fundamental chemical concepts that govern drug action; however, it will not discuss every drug or drug class.
Through conceptual discussions, examples, and applications, the text should provider with the knowledge
and skills to discuss the pertinent chemistry of drug molecules”—Provided by publisher.
Identifiers: LCCN 2022045379 (print) | LCCN 2022045380 (ebook) | ISBN 9781585286942 (paperback) | ISBN
9781585286959 (adobe pdf) | ISBN 9781585286966 (epub)
Subjects: MESH: Chemistry, Pharmaceutical | Drug Interactions | Examination Questions
Classification: LCC RS403 (print) | LCC RS403 (ebook) | NLM QV 18.2 | DDC 615.1/90076—dc23/eng/20221019
LC record available at https://lccn.loc.gov/2022045379
LC ebook record available at https://lccn.loc.gov/2022045380
© 2023, American Society of Health-System Pharmacists, Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval
system, without written permission from the American Society of Health-System Pharmacists.
ASHP is a service mark of the American Society of Health-System Pharmacists, Inc.; registered in the U.S.
Patent and Trademark Office.
ISBN: 978-1-58528-694-2 (paperback)
ISBN: 978-1-58528-695-9 (adobe pdf)
ISBN: 978-1-58528-696-6 (ePub)
DOI: 10.37573/9781585286959
10 9 8 7 6 5 4 3 2 1
 DEDICATION

To our students who blessed us with their joy, presented

us with their challenges, and made us better
educators.
To our colleagues who provided us with their
encouragement and inspiration, and who have served
as our role models.
 BASIC CONCEPTS IN MEDICINAL CHEMISTRY vii

TABLE OF CONTENTS

Acknowledgments..........................................................................................................ix
Preface............................................................................................................................xi
Abbreviations Used in This Text....................................................................................xiii

Chapter 1: Introduction����������������������������������������������������������������������������������������������������������������1
Chapter 2: Functional Group Characteristics and Roles�������������������������������������������������������� 15
Chapter 3: Identifying Acidic and Basic Functional Groups�������������������������������������������������� 51
Chapter 4: Solving pH and pKa Problems��������������������������������������������������������������������������������85
Chapter 5: Salts and Solubility����������������������������������������������������������������������������������������������� 127
Chapter 6: Drug Binding Interactions������������������������������������������������������������������������������������ 165
Chapter 7: Stereochemistry and Drug Action����������������������������������������������������������������������209
Chapter 8: Drug Metabolism��������������������������������������������������������������������������������������������������243
Chapter 9: Structure Activity Relationships and Basic Concepts in Drug Design��������������311
Chapter 10: Whole Molecule Drug Evaluation���������������������������������������������������������������������359

Appendix: Answers to Chapter Questions���������������������������������������������������������������������������� 391

Index ����������������������������������������������������������������������������������������������������������������������������������������509

DOI 10.37573/9781585286959.FM
 BASIC CONCEPTS IN MEDICINAL CHEMISTRY ix

ACKNOWLEDGMENTS

The writing and publishing of this text could not have been accomplished without the hard work and
the support of others. Marc and Robin would first like to thank the following individuals from the
American Society of Health-System Pharmacists: Jack Bruggeman, Elaine Jimenez, Lori Justice, Ryan
Owens, and Johnna Hershey. These individuals provided us with an opportunity to publish this third
edition and were extremely valuable during the revision, submission, and publication processes.
They also granted us a one year extension for the submission of this text due to a phenomenon that
starts with the letter “P!” We would also like to thank Cole Bowman from KnowledgeWorks Global
Ltd. for her work in serving as the coordinator for the production of this text. Finally, we are thankful
to our students and our peers whose comments and suggestions helped us to provide an updated
and improved version of this textbook.
Marc would like to thank the Duquesne University School of Pharmacy for providing the time
and support required for the writing of this third edition; his colleagues who took the time to provide
suggestions for various aspects of this text; his wife Barbara for her love and support and for coining
the phrase “Structure Analysis Checkpoint” introduced in the second edition; and God for His count-
less blessings and constant guidance.
Robin would like to acknowledge the two independent pharmacists who shared their world of
community pharmacy and who gingerly pointed out that Medicinal Chemistry isn’t “spoken” in this
setting. Her experience as a pharmacy technician for these two pharmacists reshaped her teaching
philosophy and as a result, her approach to drug structure evaluation. LAM and BLC constantly
demonstrated the value of questioning students—whether verbally or via practice sets. As a result,
the development of scores of practice sets, as well as a highly interactive teaching style became
central to her teaching philosophy. As always, the unwavering support of my colleagues and family
was truly appreciated, as they watched yet another ball added to an ever-evolving juggling act.

DOI 10.37573/9781585286959.FM
 BASIC CONCEPTS IN MEDICINAL CHEMISTRY xi

PREFACE

Welcome to the third edition of Basic Concepts in Medicinal Chemistry. We are excited to be able
to offer this updated version of our original text. Similar to what we experienced with our second
edition, our students, readers, and peers provided us with challenges to enhance this textbook and
provide additional explanations and examples. In hindsight, and with a critical review, we identified
topic areas that needed additional clarification. While the basic concepts that underlie medicinal
chemistry remain the same, the presentation of some of these concepts can always be improved. In
this edition, we have sought to provide better examples, better explanations, additional summaries,
and additional knowledge links to help those seeking to master these concepts. We are thankful for
the feedback that we have received from both students and peers and have worked to address the
suggestions and questions provided.
The major revisions provided in this edition include
yy A revision of all of the figures and structures to allow for a more consistent “look” through-
out the text
yy A revision of a number of the examples throughout the text to include a wider range of
drugs and drug classes
yy A clarification of examples that were potentially confusing
yy The creation of additional summary tables in Chapters 3 and 6 to help readers better select
the proper drug binding interaction
yy The addition of enhanced explanations, discussions, and examples in the following areas:
yy resonance, induction, and electron flow (Chapter 2)
yy discussion of pKa ranges of acidic and basic functional groups with a specific emphasis
on the differences seen among carboxylic acids, amines, and aromatic nitrogen atoms
(Chapter 3)
yy specific links that tie together ionization states and possible binding interactions
(Chapter 6)
yy the importance of properly identifying a drug binding interaction (Chapter 6)
yy certain metabolic transformations that can cause confusion (Chapter 8)
yy The addition of an expanded discussion of pharmacogenomics (or pharmacogenetics) in
Chapter 8, including a number of specific examples
Similar to previous editions, this text focuses on the basic, fundamental concepts governing the
discipline of medicinal chemistry and emphasizes functional group analysis and the fundamentals of
drug structure evaluation. Every drug that is prescribed and dispensed is a chemical structure that
contains numerous functional groups oriented in a specific manner. These functional groups deter-
mine the interactions of a drug molecule with its biological target, its pharmacological action(s),
the route(s) by which it is administered, the extent to which it is metabolized, and the presence or
absence of specific adverse drug reactions or drug interactions. It thus seemed appropriate to begin
the text with a discussion of the common characteristics and roles of functional groups. Subsequent
chapters were then designed to focus upon specific aspects of these functional groups. These include
the identification of acidic and basic functional groups, the use of the Henderson-Hasselbalch equa-
tion to solve quantitative and qualitative pH and pKa problems, the formation of inorganic and
organic salts of specific functional groups, the roles of water and lipid soluble functional groups and

DOI 10.37573/9781585286959.FM
xii  BASIC CONCEPTS IN MEDICINAL CHEMISTRY

the need for a proper balance of solubility, the interaction of functional groups with their biologi-
cal targets, the stereochemical orientations of functional groups within a drug molecule, and the
routes of metabolism that are available for specific functional groups. The final two chapters serve
as capstones for the text. Chapter 9 focuses upon structure activity relationships (SARs) and a brief
overview of some of the common strategies employed in rational drug design, while Chapter 10
introduces the concept of Whole Molecule Drug Evaluation, an idea that we first introduced and
published in our Medicinal Chemistry Self Assessment text in 2015.
Several aspects of this text should help students develop a strong foundation in the concepts
that govern the discipline of medicinal chemistry. Chapters 2 through 9 contain specific learning
objectives that coincide with the key concepts discussed in the chapters. The organization of the
subject material was chosen to allow students to incrementally increase their knowledge of the
functional groups that comprise drug molecules and their importance to drug therapy. Each chapter
contains numerous examples to help illustrate each key concept. In choosing these examples, a
conscious effort was made to try to include as many different commercially available drugs as pos-
sible. During the many years that the two of us have taught medicinal chemistry, a question that we
are commonly asked is, “Why is this important to a pharmacist and the practice of pharmacy?” To
address this question, each chapter includes extended discussions that link fundamental medicinal
chemistry concepts to their therapeutic relevance.
We firmly belief that these concepts are difficult to learn and master without multiple forms
of self-assessment. To better meet this need, we introduced Structure Analysis Checkpoint (SAC)
questions in the second edition of our text. These questions “follow” two drugs, venetoclax and
elamipretide, throughout the text. As new concepts and skills are introduced in each chapter,
these drugs are revisited, and readers are asked to apply their newly acquired knowledge to these
two drugs. By the end of the text, readers will have encountered over 30 unique questions for each
of these drugs and will have ultimately completed two whole molecule drug evaluations. It is impor-
tant to note that the SAC questions are based solely on two drugs, whereas the stand-alone end-of-
chapter Review Questions purposely use different drugs for each question. Each set of end-of-chapter
Review Questions was evaluated to determine if question format and/or question drug example
should be retained or changed. Modifications to the review questions (∼50%) were made in nearly
all chapters. Items were added to reflect the new content, and the total number of questions in each
chapter was increased. This provides instructors with an enhanced question bank for every chapter.
Additionally, we introduced four additional Whole Molecule Drug Evaluations in Chapter 10, increas-
ing the content in this chapter by 50%. Each Whole Molecule Drug Evaluation is unique and requires
a specific level of evaluation. The answers for all questions are provided in an appendix; however, it
is strongly suggested that readers attempt to answer the questions prior to consulting the answers.
We are thankful for the opportunity to provide you with what we believe is an updated and
improved version of our initial text, for the invaluable contributions provided by our students and
peers, and for those who have chosen to use this text to further their knowledge in the area of
medicinal chemistry.

Marc W. Harrold
Robin M. Zavod
 BASIC CONCEPTS IN MEDICINAL CHEMISTRY xiii

ABBREVIATIONS USED IN THIS TEXT

Many of these are defined in the chapters in which they appear, but a comprehensive list of all
abbreviations used in the text is provided here for your convenience.

ACE Angiotensin converting enzyme

ADH Alcohol dehydrogenase
ADME Absorption, distribution, metabolism, excretion
ADP Adenosine diphosphate
ALDH Aldehyde dehydrogenase
ALL Acute lymphoblastic leukemia
AMP Adenosine monophosphate
ARB Angiotensin II receptor blocker (aka angiotensin II receptor antagonist)
ATP Adenosine triphosphate
APS Adenosine-5′-phosphosulfate
BID bis in die (Latin for twice daily)
BPH Benign prostatic hyperplasia
CIP Cahn-Ingold-Prelog
cLog P Calculated log P
CoA Coenzyme A
CNS Central nervous system
COMT Catechol-O-methyltransferase
COPD Chronic obstructive pulmonary disease
COX Cyclooxygenase
CYP450 Cytochrome P450
1,4-DHP 1,4-Dihydropyridine
DNA Deoxyribonucleic acid
E (isomer) Entgegen (German for opposite)
EDTA Ethylenediaminetetraacetic acid
FAD Flavin adenine dinucleotide
FDA Food and Drug Administration
FMO Flavin monooxygenase
GERD Gastroesophageal reflux disease
GI Gastrointestinal
GMP Guanosine monophosphate
GTP Guanosine triphosphate
GSH Glutathione
HDL High density lipoprotein
HIV Human immunodeficiency virus
HIV-1 Human immunodeficiency virus type 1
HMG-CoA 3-Hydroxy-3-methylglutaryl coenzyme A

DOI 10.37573/9781585286959.FM
xiv  BASIC CONCEPTS IN MEDICINAL CHEMISTRY

IM Intramuscular
IMP Inosine monophosphate
IR Infrared
IUP Intrauterine device
IV Intravenous
LDL Low density lipoprotein
Log D Logarithmic expression of the distribution coefficient
Log P Logarithmic expression of the partition coefficient
LTC4 Leukotriene C4
LTD4 Leukotriene D4
LTE4 Leukotriene E4
MMAE Monomethylauristatin E
MTT Methyl-tetrazole-thiomethyl
NADH Nicotinamide adenine dinucleotide (reduced form)
NAD +
Nicotinamide adenine dinucleotide (oxidized form)
NAPDH Nicotinamide adenine dinucleotide phosphate (reduced form)
NADP +
Nicotinamide adenine dinucleotide phosphate (oxidized form)
NAT N-Acetyltransferase
NMR Nuclear magnetic resonance
NPH insulin Neutral protamine Hagedorn insulin (aka isophane insulin)
NSAID Nonsteroidal anti-inflammatory drug
OTC Over-the-counter
Pi Phosphate (inorganic)
PABA para-Aminobenzoic acid
PAH Pulmonary arterial hypertension
2-PAM Pralidoxime chloride (aka 2-Pyridine aldoxime methyl chloride)
PAP 3′-Phosphoadenosine-5′-phosphate
PAPS 3′-Phosphoadenosine-5′-phosphosulfate
PAR-1 Protease-activated receptor-1
PEG Polyethylene glycol
Pen VK Potassium penicillin V
PGE2 Prostaglandin E2
PGI2 Prostaglandin I2 (aka prostacyclin)
pH Negative log of the hydrogen ion concentration in a solution
pKa Negative log of the Ka, the dissociation constant for an acid in an aque-
ous environment
PO per os (Latin for once daily)
POMT Phenol-O-methyltransferase
PPARα Peroxisome proliferator-activated receptor
PPi Pyrophosphate (inorganic)
PRPP 5-Phosphoribosyl 1-pyrophosphate
QID quater in die (Latin for four times daily)
 BASIC CONCEPTS IN MEDICINAL CHEMISTRY xv

R (isomer) Rectus (Latin for right)

RNA Ribonucleic acid
S (isomer) Sinister (Latin for left)
SAM S-Adenosylmethionine
SAR Structure activity relationship
SC Subcutaneous
SULT Sulfotransferase
T3 Liothyronine (aka triiodothyronine)
T4 Levothyroxine
TID ter in die (Latin for three times daily)
T-IMP Thioinosine monophosphate
tRNA Transfer ribonucleic acid
TXA2 Thromboxane A2
UDP Uridine diphosphate
UDPGA UDP-glucuronic acid
UGT UDP-glucuronyltransferase
VEGF-2 Vascular endothelin growth factor 2
Z (isomer) Zusammen (German for together)
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