The Organic Chemistry of Drug Design and Drug Action

521 Pages·2015·17.71 MB·English

by  Richard B. Silverman and Mark W. Holladay (Auth.)

The Organic Chemistry of
Drug Design and Drug Action
Third Edition
Richard B. Silverman
Northwestern University
Department of Chemistry
Department of Molecular Biosciences
Chemistry of Life Processes Institute
Center for Molecular Innovation and Drug Discovery
Evanston, Illinois, USA
Mark W. Holladay
Ambit Biosciences Corporation
Departments of Drug Discovery and Medicinal Chemistry
San Diego, California, USA
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Library of Congress Cataloging-in-Publication Data
Silverman, Richard B., author.
The organic chemistry of drug design and drug action. -- Third edition / Richard B. Silverman, Mark W. Holladay.
pages cm
Includes bibliographical references and index.
ISBN 978-0-12-382030-3 (alk. paper)
1. Pharmaceutical chemistry. 2. Bioorganic chemistry. 3. Molecular pharmacology. 4. Drugs--Design. I. Holladay, Mark W.,
author. II. Title.
RS403.S55 2014
615.1’9--dc23
2013043146
British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British Library
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ISBN: 978-0-12-382030-3
Dedications
RBS
To the memory of Mom and Dad, for their love,
their humor, their ethics, and their inspiration.
To Barbara, Matt, Mar, Phil, Andy, Brooke, Alexander,
Owen, Dylan, and, hopefully, more to come,
for making life a complete joy.
MWH
To my wonderful wife, Carol, and our awesome kids,
Tommy and Ruth.
Preface to the First Edition
From 1985 to 1989, I taught a one-semester course in briefly discussed or are referenced in the general readings
medicinal chemistry to senior undergraduates and first-year section at the end of each chapter. Depending on the degree
graduate students majoring in chemistry or biochemistry. of in-depthness that is desired, this text could be used for a
Unlike standard medicinal chemistry courses that are gen- one-semester or a full-year course. The references cited can
erally organized by classes of drugs, giving descriptions of be ignored in a shorter course or can be assigned for more
their biological and pharmacological effects, I thought there detailed discussion in an intense or full-year course. Also,
was a need to teach a course based on the organic chemi- not all sections need to be covered, particularly when mul-
cal aspects of medicinal chemistry. It was apparent then, tiple examples of a particular principle are described. The
and still is the case now, that there is no text that concen- instructor can select those examples that may be of most
trates exclusively on the organic chemistry of drug design, interest to the class. It was the intent in writing this book
drug development, and drug action. This book has evolved that the reader, whether a student or a scientist interested
to fill that important gap. Consequently, if the reader is in entering the field of medicinal chemistry, would learn to
interested in learning about a specific class of drugs, its take a rational physical organic chemical approach to drug
biochemistry, pharmacology, and physiology, he or she is design and drug development and to appreciate the chem-
advised to look elsewhere for that information. Organic istry of drug action. This knowledge is of utmost impor-
chemical principles and reactions vital to drug design and tance for the understanding of how drugs function at the
drug action are the emphasis of this text with the use of molecular level. The principles are the same regardless of
clinically important drugs as examples. Usually only one the particular receptor or enzyme involved. Once the fun-
or just a few representative examples of drugs that exem- damentals of drug design and drug action are understood,
plify the particular principle are given; no attempt has been these concepts can be applied to the understanding of the
made to be comprehensive in any area. When more than many classes of drugs that are described in classical medic-
one example is given, generally it is to demonstrate differ- inal chemistry texts. This basic understanding can be the
ent chemistry. It is assumed that the reader has taken a one- foundation for the future elucidation of drug action or the
year course in organic chemistry that included amino acids, rational discovery of new drugs that utilize organic chemi-
proteins, and carbohydrates and is familiar with organic cal phenomena.
structures and basic organic reaction mechanisms. Only
the chemistry and biochemistry background information Richard B. Silverman
pertinent to the understanding of the material in this text Evanston, Illinois
is discussed. Related, but irrelevant, background topics are April 1991
xiii
Preface to the Second Edition
In the 12 years since the first edition was written, certain omeprazole. Other changes include the use of both generic
new approaches in medicinal chemistry have appeared or names and trade names, with generic names given with their
have become commonly utilized. The basic philosophy of chemical structure, and the inclusion of problem sets and
this textbook has not changed, that is, to emphasize general solutions for each chapter.
principles of drug design and drug action from an organic The first edition of this text was written primarily for
chemical perspective rather than from the perspective of upper class undergraduate and first-year graduate students
specific classes of drugs. Several new sections were added interested in the general field of drug design and drug
(in addition to numerous new approaches, methodologies, action. During the last decade it has become quite evident
and updates of examples and references), especially in the that there is a large population, particularly of synthetic
areas of lead discovery and modification (Chapter 2). New organic chemists, who enter the pharmaceutical industry
screening approaches, including high-throughput screen- with little or no knowledge of medicinal chemistry and who
ing, are discussed, as are the concepts of privileged struc- want to learn the application of their skills to the process
tures and drug-likeness. Combinatorial chemistry, which of drug discovery. The first edition of this text provided an
was in its infancy during the writing of the first edition, introduction to the field for both students and practitioners,
evolved, became a separate branch of medicinal chemistry but the latter group has more specific interests in how to
and then started to wane in importance during the twenty- accelerate the drug discovery process. For the student read-
first century. Combinatorial chemistry groups, prevalent in ers, the basic principles described in the second edition are
almost all pharmaceutical industries at the end of the twen- sufficient for the purpose of teaching the general process of
tieth century, began to be dissolved, and a gradual return to how drugs are discovered and how they function. Among
traditional medicinal chemistry has been seen. Nonetheless, the basic principles, however, I have now interspersed
combinatorial chemistry journals have sprung up to serve many more specifics that go beyond the basics and may be
as the conduit for dissemination of new approaches in this more directly related to procedures and applications use-
area, and this along with parallel synthesis are important ful to those in the pharmaceutical industry. For example,
approaches that have been added to this edition. New sec- in Chapter 2 it is stated that “Ajay and coworkers proposed
tions on SAR by NMR and SAR by MS have also been that drug-likeness is a possible inherent property of some
added. Peptidomimetic approaches are discussed in detail. molecules,a and this property could determine which mole-
The principles of structure modification to increase oral bio- cules should be selected for screening.” The basic principle
availability and effects on pharmacokinetics are presented, is that some molecules seem to have scaffolds found in many
including log P software and “rule of five” and related ideas drugs and should be initially selected for testing. But fol-
in drug discovery. The fundamentals of molecular modeling lowing that initial statement is added more specifics: “They
and 3D-QSAR are also expanded. The concepts of inverse used a set of one- and two-dimensional parameters in their
agonism, inverse antagonism, racemic switches, and the computation and were able to predict correctly over 90% of
two-state model of receptor activation are introduced in the compounds in the Comprehensive Medicinal Chemis-
Chapter 3. In Chapter 5 efflux pumps, COX-2 inhibitors, try (CMC) database.b Another computational approach to
and dual-acting drugs are discussed; a case history of the differentiate druglike and nondruglike molecules using a
discovery of the AIDS drug ritonavir is used to exemplify scoring scheme was developed,c which was able to classify
the concepts of drug discovery of reversible enzyme inhibi- correctly 83% of the compounds in the Available Chemicals
tors. Discussions of DNA structure and function, topoi- Directory (ACD)d and 77% of the compounds in the World
somerases, and additional examples of DNA-interactive
agents, including metabolically activated agents, are new or
revised sections in Chapter 6. The newer emphasis on the aAjay; Walters, W P.; Murcko, M. A. /. Med. Chem. 1998, 41, 3314.
use of HPLC/MS/MS in drug metabolism is discussed in bThis is an electronic database of Volume 6 of Comprehensive Medicinal
Chapter 7 along with the concepts of fatty acid and cho- Chemistry (Pergamon Press) available from MDL Information systems,
Inc., San Leandro, CA 94577.
lesterol conjugation and antedrugs. In Chapter 8 a section
cSadowski, J.; Kubinyi, H. J. Med. Chem. 1998, 41, 3325.
on enzyme prodrug therapies (ADEPT, GDEPT, VDEPT)
dThe ACD is available from MDL Information systems, Inc., San Leandro,
has been added as well as a case history of the discovery of CA, and contains specialty and bulk commercially available chemicals.
xv
xvi Preface to the Second Edition
Drug Index (WDI).e A variety of other approaches have the closest reference, either the one preceding the discus-
been taken to identify druglike molecules.”f I believe that sion or just following it. Because my expertise extends only
the student readership does not need to clutter its collec- in the areas related to enzymes and the design of enzyme
tive brain with these latter specifics, but should understand inhibitors.
the basic principles and approaches; however, for those who I want to thank numerous experts who read parts or
aspire to become part of the pharmaceutical research field, whole chapters and gave me feedback for modification.
they might want to be aware of these specifics and possi- These include (in alphabetical order) Shuet-Hing Lee
bly look up the references that are cited (the instructor, for Chiu, Young-Tae Chang, William A. Denny, Perry A. Frey,
a course who believes certain specifics are important may Richard Friary, Kent S. Gates, Laurence H. Hurley, Haitao
assign the references as readings). Ji, Theodore R. Johnson, Yvonne C. Martin, Ashim K.
For concepts peripheral to drug design and drug action, Mitra, Shahriar Mobashery, Sidney D. Nelson, Daniel H.
I will give only a reference to a review of that topic in case Rich, Philippa Solomon, Richard Wolfenden, and Jian Yu.
the reader wants to learn more about it. If the instructor Your input is greatly appreciated. I also greatly appreciate
believes that a particular concept that is not discussed in the assistance of my two stellar program assistants, Andrea
detail should have more exposure to the class, further read- Massari and Clark Carruth, over the course of writing
ing can be assigned. this book, as well as the editorial staff (headed by Jeremy
To minimize errors in reference numbers, several ref- Hayhurst) of Elsevier/Academic Press.
erences are cited more than once under different endnote
numbers. Also, although multiple ideas may come from a Richard B. Silverman
single reference, the reference is only cited once; if you Still in Evanston, Illinois
want to know the origin of discussions in the text, look in May 2003
eThe WDI is from Derwent Information.
f(a) Walters, W. P.; Stahl, M. T.; Murcko, M. A. Drug Discovery Today
1998, 3, 160. (b) Walters, W. P.; Ajay; Murcko, M. A. Curr. Opin. Chem.
Biol. 1999, 3, 384. (c) Teague, S. J.; Davis, A. M.; Leeson, P. D.; Oprea,
T. Angew.Chem. Int. Ed. Engl. 1999, 38, 3743. (d) Oprea, T. I. J. Comput.-
Aided Mol. Des. 2000, 14, 251. (e) Gillet, V. J.; Willett, P. L.; Bradshaw, J.
J. Chem. Inf. Comput. Sei. 1998, 38, 165. (f) Wagener, M.; vanGeerestein, V. J.
J. Chem. Inf. Comput. Sei. 2000, 40, 280. (g) Ghose, A. K.; Viswanadhan,
V.N.; Wendoloski, J. J. J. Comb. Chem. 1999, 1, 55. (h) Xu, J.; Stevenson, J.
J. Chem. Inf. Comput. Sei. 2000, 40, Uli. (i) Muegge, I.; Heald, S. L.;
Brittelli, D. J. Med. Chem. 2001, 44, 1841. (j) Anzali, S.; Barnickel, G.;
Cezanne, B.; Krug, M.; Filimonov, D.; Poroikiv, V. J. Med. Chem. 2001,
44, 2432. (k) Brstle, M.; Beck, B.; Schindler, T.; King, W; Mitchell, T.;
Clark, T. J. Med. Chem. 2002, 45, 3345.
Preface to the Third Edition
Ten years have rolled by since the publication of the sec- As was the case for the second edition, the basic philosophy
ond edition, and the field of medicinal chemistry has under- and approach in the third edition has not changed, namely,
gone a number of changes. To aid in trying to capture the an emphasis on general principles of drug design and drug
essence of new directions in medicinal chemistry, I decided action from an organic chemistry perspective rather than
to add a coauthor for this book. Mark W. Holladay was my a discussion of specific classes of drugs. For didactic pur-
second graduate student (well, that year I took four gradu- poses, directed at the industrial medicinal chemist, more
ate students into my group, so he’s actually from my sec- depth was added to many of the discussions; however, for
ond class of graduate students), and I knew from when he the student readers, the basic principles are sufficient for
came to talk to me, he was going to be a great addition to understanding the general process of drug discovery and
the group (and to help me get tenure!). In my naivete as a drug action. For a full-year course, the more in-depth dis-
new assistant professor, I assigned Mark a thesis project to cussions may be appropriate; the professor teaching the
devise a synthesis of the newly-discovered antitumor natu- course should indicate to the class the depth of material that
ral product, acivicin, which was believed to inhibit enzymes the student is expected to digest. In addition to an update of
catalyzing amido transfer reactions from L-glutamine that all of the chapters from those in the second edition with new
are important for tumor cell growth. That would be a sen- examples incorporated, several new sections were added,
sible thesis project, but I told him that the second part of some sections were deemphasized or deleted, and other sec-
his thesis would be to study its mechanism of action, as tions were reorganized. As a result of some of the comments
Mark had indicated a desire to do both organic synthesis by reviewers of our proposal for the third edition, two signif-
and enzymology. Of course, this would be a 10-year doc- icant changes were made: we expanded Chapter 1 to make it
toral project if he really had to do that, but what did I know an overview of topics that are discussed in detail throughout
then? Mark did a remarkable job, independently working the book, and the topics of resistance and synergism were
out the total synthesis of the natural product (my proposed pulled out of their former chapters and combined, together
synthetic route at the beginning failed after the second step) with several new examples, into a new chapter, Drug Resis-
and its C-5 epimer, and he was awarded his Ph.D. for the tance and Drug Synergism (now Chapter 7). Sections on
syntheses. He moved on to do a postdoc with Dan Rich, sources of compounds for screening, including library col-
the extraordinary peptide chemist now retired from the lections, virtual screening, and computational methods, as
University of Wisconsin, and joined Abbott Laboratories well as hit-to-lead and scaffold hopping, were added; the
as a senior scientist. After 15 years at Abbott, and having sections on sources of lead compounds, fragment-based
been elected to the Volwiler Society, an elite honor society lead discovery, and molecular graphics were expanded; and
at Abbott Labs for their most valuable scientists, he decided solid-phase synthesis and combinatorial chemistry were
to move to a smaller pharmaceutical environment, first at deemphasized (all in Chapter 2). In Chapter 3, other drug-
SIDDCO, then Discovery Partners International, and now receptor interactions, cation-π and halogen bonding, were
at Ambit Biosciences. Because of his career-long associa- added, as was a section on atropisomers and a case history
tion with the pharmaceutical industry (and my knowledge of the insomnia drug suvorexant as an example of a phar-
that he was an excellent writer), I invited him to coauthor macokinetically-driven drug project. A section on enzyme
the third edition to give an industrial pharmaceutical per- catalysis in drug discovery, including enzyme synthesis,
spective. It has been a rewarding and effective collabo- was added to Chapter 4. Several new case histories were
ration. Although both of us worked equally on all of the added to Chapter 5: for competitive inhibition, the epider-
chapters, I got the final say, so any inconsistencies or errors mal growth factor receptor tyrosine kinase inhibitor erlo-
are the result of my oversight. tinib and Abelson kinase inhibitor imatinib, both anticancer
drugs, were added; for transition state analogue inhibition,
Richard B. Silverman the purine nucleoside phosphorylase inhibitors, forodesine
xvii
xviii Preface to the Third Edition
and DADMe-ImmH, both antitumor agents, were added, as 2D-QSAR section of Chapter 2; and Yaoqiu Zhu, Presi-
well as the mechanism of the multisubstrate analog inhibi- dent, MetabQuest Research and Consulting, for input on
tor isoniazid; the antidiabetes drug saxagliptin was added the metabolism methodology section of Chapter 8. The
as a case history for slow, tight-binding inhibition. A sec- unknown outside reviewers of Chapters 1, 2, and 5 made
tion on toxicophores and reactive metabolites was added to some insightful comments, which helped in strengthening
Chapter 8, and the topic of antibody-drug conjugates was those respective sections. Finally, this project would have
incorporated into Chapter 9. been much more onerous if it were not for Rick Silverman’s
As in the case of the second edition, many peripheral remarkable program assistant, Pam Beck, who spent count-
topics are noted but only a general reference is cited. If an less hours organizing and formatting text, renumbering
instructor wants to pursue that topic in more depth, addi- structures, figures, and schemes when some were added or
tional readings can be assigned. To minimize errors in ref- deleted, getting permissions, coordinating between the two
erence numbers, some references are cited more than once authors, and figuring out how to fix problems that neither
with different reference numbers. Also, when multiple ideas author wanted to deal with. We also thank the Acquisitions
are taken from the same reference, the reference is cited Editor, Katey Birtcher, the Editorial Project Manager, Jill
only once; if a statement appears not to have been refer- Cetel, and, especially, the Production Manager, Sharmila
enced, try looking at a reference just prior to or following Vadivelan, for their agility and attention to detail in getting
the discussion of that topic. the third edition in such a beautiful form.
We want to thank several experts for their input on
topics that needed some strengthening: Haitao (Mark) Ji, Richard B. Silverman
now in the Department of Chemistry at the University of Evanston, Illinois (for over 37 years!)
Utah, for assistance in 3D-QSAR and for assembling the
references for computer-based drug design methodologies Mark W. Holladay
at the end of Chapter 2; Eric Martin, Director of N ovartis San Diego, California, February, 2014
Institutes of BioMedical Research, for assistance in the
Chapter 1
Introduction
Chapter Outline
1.1. Overview 1 1.3.5.1. Potency 12
1.2. Drugs Discovered without Rational Design 2 1.3.5.2. Selectivity 12
1.2.1. Medicinal Chemistry Folklore 2 1.3.5.3. Absorption, Distribution, Metabolism, and
1.2.2. Discovery of Penicillins 3 Excretion (ADME) 13
1.2.3. Discovery of Librium 4 1.3.5.4. Intellectual Property Position 13
1.2.4. Discovery of Drugs through Metabolism Studies 5 1.3.6. Drug Development 13
1.2.5. Discovery of Drugs through Clinical Observations 6 1.3.6.1. Preclinical Development 13
1.3. Overview of Modern Rational Drug Design 7 1.3.6.2. Clinical Development (Human Clinical
1.3.1. Overview of Drug Targets 7 Trials) 14
1.3.2. Identification and Validation of 1.3.6.3. Regulatory Approval to Market the Drug 14
Targets for Drug Discovery 9 1.4. Epilogue 14
1.3.3. Alternatives to Target-Based Drug Discovery 10 1.5. General References 15
1.3.4. Lead Discovery 11 1.6. Problems 16
1.3.5. Lead Modification (Lead Optimization) 12 References 16
1.1. OVERVIEW
proteins, have become i ncreasingly important approaches to
Medicinal chemistry is the science that deals with the discov- identify new drug targets.
ery and design of new therapeutic chemicals or biochemicals Today, harnessing modern tools to conduct rational drug
and their development into useful medicines. Medicines are design is pursued intensely in the laboratories of pharmaceu-
the substances used to treat diseases. Drugs are the mole- tical and biotech industries as well as in academic institutions
cules used as medicines or as components in medicines to and research institutes. Chemistry, especially organic chem-
diagnose, cure, mitigate, treat, or prevent disease.[1] Medici- istry, is at the heart of these endeavors, from the application
nal chemistry may involve isolation of compounds from of physical principles to influence where a drug will go in the
nature or the synthesis of new molecules; investigations body and how long it will remain there, to the understanding
of the relationships between the structure of natural and/or of what the body does to the drug to eliminate it from the sys-
synthetic compounds and their biological activities; elucida- tem, to the synthetic organic processes used to prepare a new
tions of their interactions with receptors of various kinds, compound for testing, first in small quantities (milligrams)
including enzymes and DNA; the determination of their and ultimately, if successful, on multikilogram scale.
absorption, transport, and distribution properties; studies of First, however, it needs to be noted that drugs are not
the metabolic transformations of these chemicals into other generally discovered. What is more likely discovered is
chemicals, their excretion and toxicity. Modern methods for known as a lead compound (or lead). The lead is a proto-
the discovery of new drugs have evolved immensely since type compound that has a number of attractive character-
the 1960s, in parallel with phenomenal advances in organic istics, including the desired biological or pharmacological
chemistry, analytical chemistry, physical chemistry, bio- activity, but may have other undesirable characteristics, for
chemistry, pharmacology, molecular biology, and medicine. example, high toxicity, other biological activities, absorp-
For example, genomics,[2] the investigations of an organism’s tion difficulties, insolubility, or metabolism problems. The
genome (all of the organism’s genes) to identify important structure of the lead compound is, then, modified by syn-
target genes and gene products (proteins expressed by the thesis to amplify the desired activity and to minimize or
genes) and proteomics, the characterization of new proteins, eliminate the unwanted properties to a point where a drug
or the abundance of proteins, in the organism’s proteome (all candidate, a compound worthy of extensive biological and
of the proteins expressed by the genome)[3] to determine their pharmacological studies, is identified, and then a clinical
structure and/or function, often by comparison with known drug, a compound ready for clinical trials, is developed.
The Organic Chemistry of Drug Design and Drug Action. http://dx.doi.org/10.1016/B978-0-12-382030-3.00001-5
Copyright © 2014 Elsevier Inc. All rights reserved. 1
2 The Organic Chemistry of Drug Design and Drug Action
The chapters of this book describe many key facets of malaria today. Another plant called Ma Huang (now known as
modern rational drug discovery, together with the organic Ephedra sinica) was used as a heart stimulant, a diaphoretic
chemistry that forms the basis for understanding them. To pro- agent (perspiration producer), and recommended for treatment
vide a preview of the later chapters and to help put the material of asthma, hay fever, and nasal and chest congestion. It is now
in context, this chapter provides a broad overview of modern known to contain two active constituents: ephedrine, a drug that
rational drug discovery with references to later chapters where is used as a stimulant, appetite suppressant, decongestant, and
more detailed discussions can be found. Prior to launching into hypertensive agent, and pseudoephedrine, used as a nasal/sinus
an overview of modern rational drug discovery approaches, let decongestant and stimulant (pseudoephedrine hydrochloride
us first briefly take a look at some examples of drugs whose (1.1) is found in many over-the-counter nasal decongestants,
discoveries relied on circumstances other than rational design, such as Sudafed). Ephedra, the extract from E. sinica, also is
that is, by happenstance or insightful observations. used today (inadvisably) by some body builders and endurance
athletes because it promotes thermogenesis (the burning of fat)
by release of fatty acids from stored fat cells, leading to quicker
1.2. DRUGS DISCOVERED WITHOUT
conversion of the fat into energy. It also tends to increase the
RATIONAL DESIGN contractile strength of muscle fibers, which allows body build-
ers to work harder with heavier weights.
1.2.1. Medicinal Chemistry Folklore
Theophrastus in the third century B.C. mentioned opium
Medicinal chemistry, in its crudest sense, has been practiced poppy juice as an analgesic agent, and in the tenth century
for several thousand years. Man has searched for cures of A.D., Rhazes (Persia) introduced opium pills for coughs, men-
illnesses by chewing herbs, berries, roots, and barks. Some tal disorders, aches, and pains. The opium poppy, Papaver
of these early clinical trials were quite successful; however, somniferum, contains morphine (1.2), a potent analgesic agent,
not until the last 100–150 years has knowledge of the active and codeine (1.3), prescribed today as a cough suppressant. The
constituents of these natural sources been known. The earli- East Asians and the Greeks used henbane, which contains sco-
est written records of the Chinese, Indian, South American, polamine (1.4, truth serum) as a sleep inducer. Inca mail run-
and Mediterranean cultures described the therapeutic effects ners and silver miners in the high Andean mountains chewed
of various plant concoctions.[4–6] A Chinese health science coca leaves (cocaine, 1.5) as a stimulant and euphoric. The anti-
anthology called Nei Ching is thought to have been writ- hypertensive drug reserpine (1.6) was extracted by ancient Hin-
ten by the Yellow Emperor in the thirteenth century B.C., dus from the snake-like root of the Rauwolfia serpentina plant
although some believe that it was backdated by the third and was used to treat hypertension, insomnia, and insanity.
century compilers.[7] The Assyrians described on 660 clay Alexander of Tralles in the sixth century A.D. recommended
tablets 1000 medicinal plants used from 1900 to 400 B.C. the autumn crocus (Colchicum autumnale) for relief of pain of
Two of the earliest medicines were described about the joints, and it was used by Avrienna (eleventh century Per-
5100 years ago by the Chinese Emperor Shen Nung in his book sia) and by Baron Anton von Störck (1763) for the treatment of
of herbs called Pen Ts’ao.[8] One of these is Ch’ang Shan, gout. Benjamin Franklin heard about this medicine and brought
the root Dichroa febrifuga, which was prescribed for fevers. it to America. The active principle in this plant is the alkaloid
This plant contains alkaloids that are used in the treatment of colchicine (1.7), which is used today to treat gout.
H C N
CH 3
3
HO H N
O
H OH
.HCl O OR' O
NHCH
H 3
OR O
Pseudophedrine hydrochloride 1.2, Morphine (R = Rʹ = H) Scopolamine
1.1 1.3, Codeine (R = CH3, Rʹ = H) 1.4
OCH
3
H3CO OCH3
O H3CO N H H3CO
O
N
H3C N OCH3 H H OCH3 O
O H O HN
H COOC
3 OCH3 OCH3 O
O
OCH
Cocaine Reserpine 3 Colchicine
1.5 1.6 1.7