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 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

AMSTERDAM • BOSTON • HEIDELBERG • LONDON

NEW YORK • OXFORD • PARIS • SAN DIEGO
SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO
Academic Press is an imprint of Elsevier
xviii
and DADMe-ImmH, both antitumor agents, were added, as
well as the mechanism of the multisubstrate analog inhibi-
tor isoniazid; the antidiabetes drug saxagliptin was added
as a case history for slow, tight-binding inhibition. A sec-
tion on toxicophores and reactive metabolites was added to
­Chapter 8, and the topic of antibody-drug conjugates was
incorporated into Chapter 9.
As in the case of the second edition, many peripheral
topics are noted but only a general reference is cited. If an
instructor wants to pursue that topic in more depth, addi-
tional readings can be assigned. To minimize errors in ref-
erence numbers, some references are cited more than once
with different reference numbers. Also, when multiple ideas
are taken from the same reference, the reference is cited
only once; if a statement appears not to have been refer-
enced, try looking at a reference just prior to or following
the discussion of that topic.
We want to thank several experts for their input on
topics that needed some strengthening: Haitao (Mark) Ji,
now in the Department of Chemistry at the University of
Utah, for assistance in 3D-QSAR and for assembling the
references for computer-based drug design ­methodologies
at the end of Chapter 2; Eric Martin, Director of N ­ ovartis
Institutes of BioMedical Research, for assistance in the
Preface to the Third Edition
2D-QSAR section of Chapter 2; and Yaoqiu Zhu, Presi-
dent, MetabQuest Research and Consulting, for input on
the metabolism methodology section of Chapter 8. The
unknown outside reviewers of Chapters 1, 2, and 5 made
some insightful comments, which helped in strengthening
those respective sections. Finally, this project would have
been much more onerous if it were not for Rick Silverman’s
remarkable ­program assistant, Pam Beck, who spent count-
less hours organizing and formatting text, renumbering
structures, ­figures, and schemes when some were added or
deleted, getting permissions, coordinating between the two
authors, and figuring out how to fix problems that neither
author wanted to deal with. We also thank the Acquisitions
Editor, Katey Birtcher, the Editorial Project Manager, Jill
Cetel, and, especially, the Production Manager, Sharmila
Vadivelan, for their agility and attention to detail in getting
the third edition in such a beautiful form.
Richard B. Silverman
Evanston, Illinois (for over 37 years!)
Mark W. Holladay
San Diego, California, February, 2014

Introduction
Chapter Outline
1.1. Overview
1.2. Drugs Discovered without Rational Design
1.2.1. Medicinal Chemistry Folklore
1.2.2. Discovery of Penicillins
1.2.3. Discovery of Librium
1.2.4. Discovery of Drugs through Metabolism Studies
1.2.5. Discovery of Drugs through Clinical Observations 6
1.3. Overview of Modern Rational Drug Design
1.3.1. Overview of Drug Targets
1.3.2. Identification and Validation of
Targets for Drug Discovery
1.3.3. Alternatives to Target-Based Drug Discovery
1.3.4. Lead Discovery
1.3.5. Lead Modification (Lead Optimization)
1.1. OVERVIEW
Medicinal chemistry is the science that deals with the discov-
ery and design of new therapeutic chemicals or biochemicals
and their development into useful medicines. Medicines are
the substances used to treat diseases. Drugs are the mole-
cules used as medicines or as components in medicines to
diagnose, cure, mitigate, treat, or prevent disease.[1] Medici-
nal chemistry may involve isolation of compounds from
nature or the synthesis of new molecules; investigations
of the relationships between the structure of natural and/or
synthetic compounds and their biological activities; elucida-
tions of their interactions with receptors of various kinds,
including enzymes and DNA; the determination of their
absorption, transport, and distribution properties; studies of
the metabolic transformations of these chemicals into other
chemicals, their excretion and toxicity. Modern methods for
the discovery of new drugs have evolved immensely since
the 1960s, in parallel with phenomenal advances in organic
chemistry, analytical chemistry, physical chemistry, bio-
chemistry, pharmacology, molecular biology, and medicine.
For example, genomics,[2] the investigations of an organism’s
genome (all of the organism’s genes) to identify important
target genes and gene products (proteins expressed by the
genes) and proteomics, the characterization of new proteins,
or the abundance of proteins, in the organism’s proteome (all
of the proteins expressed by the genome)[3] to determine their
structure and/or function, often by comparison with known
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.
Chapter 1
1 1.3.5.1. Potency 12
2 1.3.5.2. Selectivity 12
2 1.3.5.3. Absorption, Distribution, Metabolism, and
3 Excretion (ADME) 13
4 1.3.5.4. Intellectual Property Position 13
5 1.3.6. Drug Development 13
1.3.6.1. Preclinical Development 13
7 1.3.6.2. Clinical Development (Human Clinical
7 Trials)14
1.3.6.3. Regulatory Approval to Market the Drug 14
9 1.4. Epilogue 14
10 1.5. General References 15
11 1.6. Problems 16
12 References 16
proteins, have become i­ncreasingly important approaches to
identify new drug targets.
Today, harnessing modern tools to conduct rational drug
design is pursued intensely in the laboratories of pharmaceu-
tical and biotech industries as well as in academic institutions
and research institutes. Chemistry, especially organic chem-
istry, is at the heart of these endeavors, from the application
of physical principles to influence where a drug will go in the
body and how long it will remain there, to the understanding
of what the body does to the drug to eliminate it from the sys-
tem, to the synthetic organic processes used to prepare a new
compound for testing, first in small quantities (milligrams)
and ultimately, if successful, on multikilogram scale.
First, however, it needs to be noted that drugs are not
generally discovered. What is more likely discovered is
known as a lead compound (or lead). The lead is a proto-
type compound that has a number of attractive character-
istics, including the desired biological or pharmacological
activity, but may have other undesirable characteristics, for
example, high toxicity, other biological activities, absorp-
tion difficulties, insolubility, or metabolism problems. The
structure of the lead compound is, then, modified by syn-
thesis to amplify the desired activity and to minimize or
eliminate the unwanted properties to a point where a drug
candidate, a compound worthy of extensive biological and
pharmacological studies, is identified, and then a clinical
drug, a compound ready for clinical trials, is developed.
1
2 The Organic Chemistry of Drug Design and Drug Action

The chapters of this book describe many key facets of
modern rational drug discovery, together with the organic
chemistry that forms the basis for understanding them. To pro-
vide a preview of the later chapters and to help put the material
in context, this chapter provides a broad overview of modern
rational drug discovery with references to later chapters where
more detailed discussions can be found. Prior to launching into
an overview of modern rational drug discovery approaches, let
us first briefly take a look at some examples of drugs whose
discoveries relied on circumstances other than rational design,
that is, by happenstance or insightful observations.
1.2. DRUGS DISCOVERED WITHOUT
RATIONAL DESIGN
1.2.1. Medicinal Chemistry Folklore
Medicinal chemistry, in its crudest sense, has been practiced
for several thousand years. Man has searched for cures of
illnesses by chewing herbs, berries, roots, and barks. Some
of these early clinical trials were quite successful; however,
not until the last 100–150 years has knowledge of the active
constituents of these natural sources been known. The earli-
est written records of the Chinese, Indian, South American,
and Mediterranean cultures described the therapeutic effects
of various plant concoctions.[4–6] A Chinese health science
anthology called Nei Ching is thought to have been writ-
ten by the Yellow Emperor in the thirteenth century B.C.,
although some believe that it was backdated by the third
century compilers.[7] The Assyrians described on 660 clay
tablets 1000 medicinal plants used from 1900 to 400 B.C.
Two of the earliest medicines were described about
5100 years ago by the Chinese Emperor Shen Nung in his book
of herbs called Pen Ts’ao.[8] One of these is Ch’ang Shan,
the root Dichroa febrifuga, which was prescribed for fevers.
This plant contains alkaloids that are used in the treatment of
malaria today. Another plant called Ma Huang (now known as
Ephedra sinica) was used as a heart stimulant, a diaphoretic
agent (perspiration producer), and recommended for treatment
of asthma, hay fever, and nasal and chest congestion. It is now
known to contain two active constituents: ephedrine, a drug that
is used as a stimulant, appetite suppressant, decongestant, and
hypertensive agent, and pseudoephedrine, used as a nasal/sinus
decongestant and stimulant (pseudoephedrine hydrochloride
(1.1) is found in many over-the-counter nasal decongestants,
such as Sudafed). Ephedra, the extract from E. sinica, also is
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
conversion of the fat into energy. It also tends to increase the
contractile strength of muscle fibers, which allows body build-
ers to work harder with heavier weights.
Theophrastus in the third century B.C. mentioned opium
poppy juice as an analgesic agent, and in the tenth century
A.D., Rhazes (Persia) introduced opium pills for coughs, men-
tal disorders, aches, and pains. The opium poppy, Papaver
somniferum, contains morphine (1.2), a potent analgesic agent,
and codeine (1.3), prescribed today as a cough suppressant. The
East Asians and the Greeks used henbane, which contains sco-
polamine (1.4, truth serum) as a sleep inducer. Inca mail run-
ners and silver miners in the high Andean mountains chewed
coca leaves (cocaine, 1.5) as a stimulant and euphoric. The anti-
hypertensive drug reserpine (1.6) was extracted by ancient Hin-
dus from the snake-like root of the Rauwolfia serpentina plant
and was used to treat hypertension, insomnia, and insanity.
Alexander of Tralles in the sixth century A.D. recommended
the autumn crocus (Colchicum autumnale) for relief of pain of
the joints, and it was used by Avrienna (eleventh century Per-
sia) and by Baron Anton von Störck (1763) for the treatment of
gout. Benjamin Franklin heard about this medicine and brought
it to America. The active principle in this plant is the alkaloid
colchicine (1.7), which is used today to treat gout.

CH3 H3C N
HO H N
O
H OH
.HCl O O
OR'
H NHCH3
OR O
Pseudophedrine hydrochloride 1.2, Morphine (R = Rʹ = H) Scopolamine
1.1 1.3, Codeine (R = CH3, Rʹ = H) 1.4
OCH3
H3CO OCH3
H3CO N
O H H3CO
N H O
H3C N OCH3 H OCH3 O
O H O HN
H3COOC OCH3
OCH3
O O
OCH3
Cocaine Reserpine Colchicine
1.5 1.6 1.7
Chapter | 1 Introduction 3

FIGURE 1.1 Parody of drugs discovered without rational design.

In 1633, a monk named Calancha, who accompanied the refers to all of the cardiac glycosides, is still manufactured
Spanish conquistadors to Central and South America, intro- by extraction of foxglove and related plants.
duced one of the greatest herbal medicines to Europe upon
his return. The South American Indians would extract the O
cinchona bark and use it for chills and fevers; the Europe-
R O
ans used it for the same and for malaria. In 1820, the active
constituent was isolated and later determined to be qui- OH H OH
HO O O H
nine (1.8), an antimalarial drug, which also has antipyretic
(fever-reducing) and analgesic properties. H OH
O O O
H HO H
OH
Digitoxin (R = H) Digoxin (R = OH)
H 1.9 1.10
HO N
H3CO
1.2.2. Discovery of Penicillins
N In 1928, Alexander Fleming noticed a green mold growing
Quinine in a culture of Staphylococcus aureus, and where the two
1.8 had converged, the bacteria were lysed.[10] This led to the
discovery of penicillin, which was produced by the mold.
Modern therapeutics is considered to have begun with Actually, Fleming was not the first to make this observation;
an extract of the foxglove plant, which was cited by Welsh John Burdon-Sanderson had done so in 1870, ironically also
physicians in 1250, named by Fuchsius in 1542, and intro- at St. Mary’s Hospital in London, the same institution where
duced for the treatment of dropsy (now called edema) in Fleming made the rediscovery![11] Joseph Lister had treated
1785 by Withering.[5,9] The active constituents are second- a wounded patient with Penicillium, the organism later found
ary glycosides from Digitalis purpurea (the foxglove plant) to be the producer of penicillin (although the strains discov-
and Digitalis lanata, namely, digitoxin (1.9) and digoxin ered earlier than Fleming did not produce penicillin, but,
(1.10), respectively; both are important drugs for the treat- rather, another antibiotic, mycophenolic acid). After Fleming
ment of congestive heart failure. Today, digitalis, which observed this phenomenon, he tried many times to repeat it
4 The Organic Chemistry of Drug Design and Drug Action

without success; it was his colleague, Dr Ronald Hare,[12,13] For many years, there was a raging debate regarding the
who was able to reproduce the observation. It only occurred actual structure of penicillin (1.12),[17] but the correct struc-
the first time because a combination of unlikely events all took ture was elucidated in 1944 with an X-ray crystal structure
place simultaneously. Hare found that very special conditions by Dorothy Crowfoot Hodgkin (Oxford); the crystal structure
were required to produce the phenomenon initially observed was not published until after the war in 1949.[18] Several differ-
by Fleming. The culture dish inoculated by Fleming must ent penicillin analogs (R group varied) were isolated early on;
have become accidentally and simultaneously contaminated only two of these early analogs (1.12, R = PhOCH2, penicillin
with the mold spore. Instead of placing the dish in the refrig- V and 1.12, R = PhCH2, penicillin G) are still in use today.
erator or incubator when he went on vacation, as is normally
done, Fleming inadvertently left it on his lab bench. When he + + +
returned the following month, he noticed the lysed bacteria. 5 1 6 &+
Ordinarily, penicillin does not lyse these bacteria; it prevents 2 1 &+
them from developing, but it has no effect if added after the 2
&22+
bacteria have developed. However, while Fleming was on +
vacation (July–August), the weather was unseasonably cold, 3HQLFLOOLQ9 5 3K2&+
and this provided the particular temperature required for the 3HQLFLOOLQ* 5 &+3K
mold and the staphylococci to grow slowly and produce the 
lysis. Another extraordinary circumstance was that the partic-
ular strain of the mold on Fleming’s culture was a relatively
good penicillin producer, although most strains of that mold
(Penicillium) produce no penicillin at all. The mold presum-
1.2.3. Discovery of Librium
ably came from the laboratory just below Fleming’s where The first benzodiazepine tranquilizer drug, Librium
research on molds was going on at that time. (7-chloro-2-(methylamino)-5-phenyl-3H-1,4-benzodiaze-
Although Fleming suggested that penicillin could be pine 4-oxide; chlordiazepoxide HCl; 1.13), was discovered
useful as a topical antiseptic, he was not successful in serendipitously.[19]
producing penicillin in a form suitable to treat infections.
Nothing more was done until Sir Howard Florey at Oxford NHCH3. HCl
University reinvestigated the possibility of producing peni- N
cillin in a useful form. In 1940, he succeeded in producing
penicillin that could be administered topically and systemi- Cl N+
–
O
cally,[14] but the full extent of the value of penicillin was not
revealed until the late 1940s.[15] Two reasons for the delay
in the universal utilization of penicillin were the emer-
gence of the sulfonamide antibacterials (sulfa drugs, 1.11; Chlordiazepoxide HCl
see Chapter 5, Section 5.2.2.3) in 1935 and the outbreak of 1.13
World War II. The pharmacology, production, and clinical
application of penicillin were not revealed until after the Dr. Leo Sternbach at Roche was involved in a program
war to prevent the Germans from having access to this won- to synthesize a new class of tranquilizer drugs. He originally
der drug. Allied scientists, who were interrogating German set out to prepare a series of benzheptoxdiazines (1.14), but
scientists involved in chemotherapeutic research, were told when R1 was CH2NR2 and R2 was C6H5, it was found that
that the Germans thought the initial report of penicillin was the actual structure was that of a quinazoline 3-oxide (1.15).
made just for commercial reasons to compete with the sulfa However, none of these compounds gave any interesting
drugs. They did not take the report seriously. pharmacological results.

R1
H2N SO2NHR N N R1
O
X X N+ –
Sulfa drugs N O
1.11 Y R2 Y R2
1.14 1.15
The original mold was Penicillium notatum, a strain that
gave a relatively low yield of penicillin. It was replaced by The program was abandoned in 1955 in order for Stern-
Penicillium chrysogenum,[16] which had been cultured from bach to work on a different project. In 1957, during a general
a mold growing on a grapefruit in a market in Peoria, Illinois! laboratory cleanup, a vial containing what was thought to
Chapter | 1 Introduction 5

H
NHCH3
N CH2Cl N
..
CH3NH2 CH2Cl
N+ – N
Cl O Cl + O–

1.16

CH3NH2

NHCH3
N CH2NHCH3 N

N+ – .. CH2 Cl
Cl O N 1.13
Cl
OH

SCHEME 1.1 Mechanism of formation of Librium

be 1.15 (X = 7-Cl, R1 = CH2NHCH3, R2 = C6H5) was found
and, as a last effort, was submitted for pharmacological test-
ing. Unlike all of the other compounds submitted, this one
gave very promising results in six different tests used for
preliminary screening of tranquilizers. Further investigation
revealed that this compound was not a quinazoline 3-oxide,
but, rather, was the benzodiazepine 4-oxide (1.13), presum-
ably produced in an unexpected reaction of the corresponding
chloromethyl quinazoline 3-oxide (1.16) with methylamine
(Scheme 1.1). If this compound had not been found in the
laboratory cleanup, all of the negative pharmacological
results would have been reported for the quinazoline 3-oxide
class of compounds, and benzodiazepine 4-oxides may not
have been discovered for many years to come.
Penicillin V and Librium are two important drugs that
were discovered without a lead. However, once they were
identified, they then became lead compounds for second
generation analogs. There are now a myriad of penicillin-
derived antibacterials that have been synthesized as the
result of the structure elucidation of the earliest penicil-
lins. Valium (diazepam, 1.17) was synthesized at Roche
even before Librium was introduced onto the market; this
drug was derived from the lead compound, Librium, and is
almost 10 times more potent than the lead.
CH3
O CH3
N
1.2.4. Discovery of Drugs through
Metabolism Studies
During drug metabolism studies (Chapter 7), metabolites
(drug degradation products generated in vivo) that are
isolated are screened to determine if the activity observed
is derived from the drug candidate or from a metabolite.
For example, the anti-inflammatory drug sulindac (1.18;
Clinoril) is not the active agent; the metabolic reduction
product (1.19) is responsible for the activity.[20] The non-
sedating antihistamine terfenadine (1.20; Seldane) was
found to cause an abnormal heart rhythm in some users
who also were taking certain antifungal agents, which
were found to block the enzyme that metabolizes terfena-
dine. This caused a build-up of terfenadine, which led to
the abnormal heart rhythms (Chapter 7). Consequently,
Seldane was withdrawn from the market. However, a
metabolite of terfenadine, fexofenadine (1.21; Allegra),
was also found to be a nonsedating antihistamine, but
it can be metabolized even in the presence of antifun-
gal agents. This, then, is a safer drug and was approved
by the Food and Drug Administration (FDA) to replace
Seldane.
COOH COOH
F F
CH3

Cl N
O S

CH3 S
Diazepam Sulindac CH3
1.17 1.18 1.19
6 The Organic Chemistry of Drug Design and Drug Action

CH3
CH3 COOH
CH3 CH3
. HCl CH3 Ph HCl
Ph
HO N HO N
Ph OH Ph OH
Terfenadine HCl Fexofenadine HCl
1.20 1.21

1.2.5. Discovery of Drugs through Clinical
Observations
Sometimes a drug candidate during clinical trials will
exhibit more than one pharmacological activity, that is, it
may produce a side effect. This compound, then, can be
used as a lead (or, with luck, as a drug) for the secondary
activity. In 1947, an antihistamine, dimenhydrinate (1.22;
Dramamine) was tested at the allergy clinic at Johns Hop-
kins University and was found also to be effective in reliev-
ing a patient who suffered from car sickness; a further study
proved its effectiveness in the treatment of seasickness[21]
and airsickness.[22] It then became the most widely used
drug for the treatment of all forms of motion sickness.
O N
H EtO HN
CH3
Ph O N N
NMe2 • Cl
Ph N N
O
CH3
Dimenhydrinate
1.22
There are other popular examples of drugs derived from
clinical observations. Bupropion hydrochloride (1.23), an
antidepressant drug (Wellbutrin), was found to help patients
stop smoking and became the first drug marketed as a smoking
cessation aid (Zyban). The impotence drug sildenafil citrate
(1.24; Viagra) was designed for the treatment of angina and
hypertension by blocking the enzyme phosphodiesterase-5,
which hydrolyzes cyclic guanosine monophosphate (cGMP),
a vasodilator that allows increased blood flow.[23] In 1991,
sildenafil went into Phase I clinical trials for angina. In Phase
II clinical trials, it was not as effective against angina as Pfizer
had hoped, so it went back to Phase I clinical trials to see how
high of a dose could be tolerated. It was during that clinical
trial that the volunteers reported increased erectile function.
Given the weak activity against angina, it was an easy deci-
sion to try to determine its effectiveness as the first treatment
for erectile dysfunction. Sildenafil works by the mechanism
for which it was designed as an antianginal drug, except it
inhibits the phosphodiesterase in the penis (phosphodiester-
ase-5) as well as the one in the heart (Figure 1.2).
O CH3
N
O N
HN HCl O2S
HO
N
Cl N HO2C CO2H 2
CH3
Bupropion HCl Sildenafil citrate
1.23 1.24
Sexual stimulation causes release of nitric oxide in the
penis. Nitric oxide is a second messenger molecule that turns
on (pun intended) the enzyme guanylate cyclase, which con-
verts guanosine triphosphate to cGMP. The vasodilator cGMP

L-Arg NO
Nitric oxide
Synthase
Stimulates
Erection
Guanylate cyclase

GTP Smooth Increased

cGMP muscle blood
relaxation flow

GMP Vasoconstriction
PDE 5

Inhibits
Viagra
FIGURE 1.2 Mechanism of action of sildenafil (Viagra)
Chapter | 1 Introduction 7

relaxes the smooth muscle in the corpus cavernosum, allowing
blood to flow into the penis, thereby producing an erection.
However, phosphodiesterase-5 (PDE-5) hydrolyzes the cGMP,
which causes vasoconstriction and the outflow of blood from
the penis. Sildenafil inhibits this phosphodiesterase, preventing
the hydrolysis of cGMP and prolonging the vasodilation effect.
1.3. OVERVIEW OF MODERN RATIONAL
DRUG DESIGN
The two principal origins of modern pharmaceutical indus-
tries are apothecaries, which initiated wholesale production
of drugs in the mid-nineteenth century, and dye and chemi-
cal companies that were searching for medical applications
for their products in the late nineteenth century.[24] Merck
started as a small apothecary shop in Germany in 1668 and
started wholesale production of drugs in the 1840s. Other
drug companies, such as Schering, Hoffmann-La Roche,
Burroughs Wellcome, Abbott, Smith Kline, Eli Lilly, and
Squibb, also started as apothecaries in the nineteenth cen-
tury. Bayer, Hoechst, Ciba, Geigy, Sandoz, and Pfizer began
as dye and chemical manufacturers.
During the middle third of the twentieth century, anti-
biotics, such as sulfa drugs and penicillins (Section 1.2.2),
Drug Preclinical &
target
Lead Lead
clinical
Regulatory
discovery modification approval
selection development
FIGURE 1.3 Typical stages of modern rational drug discovery and
development
antihistamines, hormones, psychotropics, and vaccines
were invented or discovered. Death in infancy was cut by
50% and maternal death from infection during childbirth
decreased by 90%. Tuberculosis, diphtheria, and pneu-
monia could be cured for the first time in history. These
advances mark the beginning of the remarkable discoveries
made today, not only in the pharmaceutical industry but also
in academic and government laboratories.
Figure 1.3 shows the typical stages of modern ratio-
nal drug discovery and development. Below we present an
overview of each of these steps to provide context for the
concepts discussed in subsequent chapters. Among these
topics, the interactions of drugs with their targets, the ratio-
nale and approaches to lead discovery, and the strategies
underlying lead modification have a strong basis in physical
and mechanistic organic chemistry and, hence, will be the
central themes of subsequent chapters.
1.3.1. Overview of Drug Targets
The majority of drugs exert their effects through interac-
tions with specific macromolecules in the body. Many of
these macromolecular drug targets are proteins. You may
recall that proteins are long polymer chains of amino acid
residues that can loop and fold to produce grooves, cavi-
ties, and clefts that are ideal sites for interactions with
other large or small molecules (Figure 1.4). Other drugs
exert their effects by interacting with a different class of
macromolecules called nucleic acids, which consist of long
chains of nucleotide residues. Figure 1.5 shows the model

FIGURE 1.4 Small molecule drug (quinpirol) bound to its protein target (dopamine D3 receptor). The cartoon on the right shows how a protein, such as
the D3 receptor, spans the membrane of a cell. The D3 receptor in red depicts its conformation when the drug is bound. The D3 receptor in yellow depicts
its conformation when no drug is bound. “TM” designates a transmembrane domain of the protein. Note the significant differences between the red and
yellow regions on the intracellular side of the membrane, prompted by the binding of quinpirol from the extracellular side (Ligia Westrich, et al. Biochem.
Pharmacol. 2010, 79, 897–907.) On the right is a molecular representation of the fluid mosaic model of a biomembrane structure. From Singer, S. J.;
Nicolson, G L. Science. 1972, 175, 720. Reprinted with permission from AAAS.
8 The Organic Chemistry of Drug Design and Drug Action

of a small molecule drug (daunomycin) interacting with a

Daunomycin
FIGURE 1.5 Small molecule drug (daunomycin) bound to its nucleic
acid target (DNA). The different colors represent C (yellow), G (green),
A (red), and T (blue). Mukherjee, A.; Lavery, R.; Bagchi, B.; Hynes, J. T.
On the molecular mechanism of drug intercalation into DNA: A computer
simulation study of the intercalation pathway, free energy, and DNA struc-
tural changes. J. Am. Chem Soc. 2008, 130, 9747. Reprinted with permis-
sion from Dr. Biman Bagchi, Indian Institute of Science, Bangalore, India.
Journal of the American Chemical Society by American Chemical Society.
Reproduced with permission of American Chemical Society in the format
republish in a book via Copyright Clearance Center.
nucleic acid target.
While some drugs form covalent bonds with their tar-
gets, in the majority of cases, including those in Figures
1.4 and 1.5, noncovalent interactions are responsible for the
affinity between the drug and the target. The main classifi-
cations of such noncovalent attractive forces are ionic inter-
actions, ion–dipole interactions, dipole–dipole interactions,
hydrogen bonding, charge–transfer complexes, hydropho-
bic interactions, cation–π interactions, halogen bonding,
and van der Waals forces. For example, a negatively charged
moiety on the drug will be attracted to a positively charged
residue on the target, or a phenyl ring on the drug will be
attracted to the hydrophobic side chains of amino acids such
as phenylalanine, leucine, valine, and others. Figure 1.6
shows schematically the multiple noncovalent interactions
of the drug zanamivir (Relenza) with its target, neuramini-
dase, an enzyme that is critical in the reproductive cycle of
the influenza virus. Figure 1.6 illustrates how multiple non-
covalent interactions can combine to result in a high affinity
of the drug for the target. Noncovalent interactions that are
important for drug–target interactions are discussed in more
detail in Chapter 3, Section 3.2.2.
Certain proteins are attractive as drug targets because of
the critical roles they play in the body (Table 1.1). Receptors
are proteins whose function is to interact with (“receive”)
another molecule (the receptor ligand), thereby inducing
the receptor to perform some further action. Many receptors
serve the role of translating signals from outside the cell to
actions inside the cell. Figure 1.4 depicts a receptor protein
that spans the membrane of a cell. The receptor ligand binds

FIGURE 1.6 Interaction of the drug zanamivir with its enzyme target neuraminidase. (a) Model derived from an X-ray crystal structure; zanamivir is
depicted as a space-filling model at center: carbon (white), oxygen (red), nitrogen (blue), and hydrogen (not shown). Only the regions of the enzyme that
are close to the inhibitor are shown: small ball and stick models show key enzyme side chains (b) Schematic two-dimensional representation showing
noncovalent interactions (dotted-lines) between zanamivir and the enzyme.
Chapter | 1 Introduction
TABLE 1.1 Important Classes of Protein Drug Targets
Important Classes of
Protein Drug Targets Role or Function
Receptors Transmit biological signals. Binding
of certain ligands stimulates receptors
to conduct a further action
Transporters Facilitate transport of substances
across cell membranes
Enzymes Catalyze the transformation of
substrate(s) to product(s)
to the region of the protein that is outside the cell, causing
changes to the region of the protein that is inside the cell,
thereby triggering further intracellular events (events inside
the cell). Depending on the disease, it may be desirable to
design drugs that either promote this trigger (receptor ago-
nists) or block it (receptor antagonists). The organic chemi-
cal basis for the design and action of drugs that promote or
inhibit the actions of receptors is discussed in more detail
in Chapter 3.
Other proteins act as transporters. These proteins also
span cell membranes, where their role is to carry or trans-
port molecules or ions from one side of the cell to the other.
Examples of drugs that modulate transporter action are dis-
cussed in Chapter 2.
Enzymes are another class of proteins that serve as very
important drug targets. The formal name of an enzyme
usually ends in the suffix “-ase”. Enzymes are biologi-
cal catalysts that facilitate the conversion of one or more
reactants (“substrates”) to one or more new products. For
example, the enzyme acetylcholinesterase catalyzes the
breakdown of the excitatory neurotransmitter acetylcholine
(Scheme 1.2), which is important for learning and memory
(among other actions). This breakdown of acetylcholine
by ­ acetylcholinesterase is the mechanism by which the
effect of acetylcholine is turned off by the body. A drug that
inhibits this enzyme should prolong the action of acetyl-
choline. Thus, for example, acetylcholinesterase inhibitors
such as rivastigmine (Exelon) have been used for treat-
ment of the symptoms of Alzheimer’s disease (Chapter 2,
­Section 2.1.2.1). Another important drug target is HMG-
CoA reductase, an enzyme in the pathway of cholesterol
biosynthesis (Scheme 1.3). Inhibitors of this enzyme serve
to reduce the production of cholesterol and are, therefore,
H3 C
O Me Acetylcholinesterase
H3C N
CH3 O O
Acetylcholine
SCHEME 1.2 Reaction catalyzed by the enzyme acetylcholinesterase
9
Acetyl CoA + Acetoacetyl CoA
HMG-CoA
HMG-CoA reductase
Mevalonate
Geranyl/farnesyl diphosphates
Presqualene diphosphate
Squalene synthase
Squalene
Cholesterol
SCHEME 1.3 Pathway for cholesterol biosynthesis showing the role of
the enzyme HMG-CoA reductase. Adapted from http://www.jneuroinflam-
mation.com/content/figures/1742-2094-4-5-1.jpg.
important drugs for patients with excessive cholesterol in
their bloodstreams (Chapter 5, Section 5.2.4.3). Note that
in the foregoing examples, enzyme inhibition was a strat-
egy to promote the action of acetylcholine (by preventing
its breakdown), but to impede the action of cholesterol (by
impeding its biosynthesis). Further examples of the organic
chemistry of enzyme inhibitor design and action are dis-
cussed throughout Chapters 4 and 5.
Nucleic acids, for example, DNA, have an important
role in cell replication, and drugs that bind to DNA can dis-
rupt this function. This mechanism is responsible for the
action of some anticancer and anti-infective drugs that dis-
rupt the replication of, respectively, cancer cells and infec-
tious organisms. The organic chemical basis for the design
and action of drugs that disrupt nucleic acid function is dis-
cussed in Chapter 6.
1.3.2. Identification and Validation of Targets
for Drug Discovery
In modern rational drug design, there are a number of key
tools useful for uncovering, or at least hypothesizing, the
role of potential drug targets in disease.[25] This exercise is
sometimes referred to as target validation although many
investigators do not consider a target truly validated until
its role in human disease has been convincingly demon-
strated in clinical trials. It has been estimated that there are
only 324 drug targets for all classes of approved drugs (266
H3C
OH HO Me
H3 C N
CH3
10
are human-genome derived proteins; the rest are patho-
gen targets) and only 1357 unique drugs, of which 1204
are small molecules and 166 are biologics.[26] Of the small
molecule drugs, only 803 can be administered orally. One
approach to identify targets related to a disease is to com-
pare the genetic make-up of a large number of patients with
the disease with that of a large number of normal patients,
and identify which genes, and therefore the corresponding
proteins, are consistently different in the two sets. Given
that there are about 20,500 genes in the human genome,[27]
there are many potential sites for mutations, leading to a
disease. However, only about 7–8% of human genes have
been explicitly associated with a disease. Another approach
is to apply one of the several methods of selectively elimi-
nating the function of a particular protein and observing
the consequence in an isolated biochemical pathway or a
whole animal.[28] Among prominent methods to achieve
this, gene knockout[29] or knockdown using small interfer-
ing RNA (siRNA) technology[30] are important ones (RNA
interference has an important role in directing the devel-
opment of gene expression). Alternatively, antibodies to a
specific protein can be developed that block the function
of the protein.[31] The direct use of siRNA as a therapeutic
agent is under intense investigation; similarly, a number of
antibodies to proteins are already in active use as therapeu-
tic agents.[32] But, at least to date, rarely do these modes of
therapy entail simply swallowing a pill once or twice a day,
so these therapies have significant limitations. Sometimes, a
small molecule that very specifically modifies the function
of a target may serve to establish the role of that target, even
if it is not itself suitable as a drug.
The more simple approach to target identification, rather
than attempting to uncover a new one, is to use a target that
has already been validated in the clinic. It has been esti-
mated that the probability of getting a compound for a
novel target into preclinical (animal) development is only
3%, but it is 17% for an established target.[33] However, the
use of a well-established target can result in me-too drugs
(drugs that are structurally very similar to already known
drugs and act by the same mechanism of action), producing
more drugs of the same class. With appropriate marketing, a
company is able to benefit economically from the “me-too”
approach although society may not realize a significant ben-
efit. On the other hand, a novel target can lead to drugs that
have novel properties that can treat diseases or subpopu-
lations of diseases not previously treated. While this latter
approach is more expensive and usually has a lower prob-
ability of success, it is also potentially more rewarding both
for society and also for the finances of the company that
established the new mechanism of treatment.
The target-based approach sometimes gives surprises
when it turns out that, after a drug is in clinical trials or on
the market, its mechanism of action is found to be com-
pletely different from what the drug was designed for. For
The Organic Chemistry of Drug Design and Drug Action
example, the cholesterol-lowering drug ezetimibe (1.25,
Zetia) was designed as an inhibitor of acyl-coenzyme A
cholesterol acyltransferase (ACAT), the enzyme that esteri-
fies cholesterol, which is required for its intestinal absorp-
tion; inhibition of ACAT should lower the absorption of
cholesterol.[34] It was found that its in vivo activity did not
correlate with its in vitro ACAT inhibition; ezetimibe was
later found to inhibit the transport of cholesterol through
the intestinal wall rather than inhibit ACAT.[35] Pregabalin
(1.26, Lyrica), a drug for the treatment of epilepsy, neuro-
pathic pain, fibromyalgia, and generalized anxiety disorder,
was found to be an activator of the enzyme glutamate decar-
boxylase in vitro, and that was thought to be responsible
for its anticonvulsant activity; the mechanism of action was
later found to be antagonism of the α2δ-subunit of a calcium
channel.[36]
OH OH
H3N COO
F
N H
O
Ezetimibe F Pregabalin
1.25 1.26
Modern rational drug discovery usually begins with
identification of a suitable biological target whose actions
may be amenable to enhancement or inhibition by a drug,
thereby leading to a beneficial therapeutic response. But
how does one start in the search for the molecule that has the
desired effect on the target? And what properties, other than
exerting the desired action on its target, must the drug have?
The typical approach is to first identify one or more lead
compounds (defined in Section 1.1), i.e. molecular start-
ing points, the structures of which can be modified (“opti-
mized”) to afford a suitable drug. In Section 1.3.4 there is
a brief overview of methods of lead discovery, followed by
a short overview of considerations underlying lead modi-
fication (Section 1.3.5). Chapter 2 will discuss the organic
chemistry behind these topics in more detail.
1.3.3. Alternatives to Target-Based Drug
Discovery
As discussed above (Sections 1.3.1 and 1.3.2), the most
common approach to drug discovery involves initial
identification of an appropriate biological target. Sams-
Dodd[37] notes that diseases can be thought of as abnormali-
ties at the mechanistic level, for example, abnormalities in
a gene, a receptor, or an enzyme. This mechanistic abnor-
mality can then result in a functional problem, for example,
an abnormal function of the mitochondria, which causes
a functional problem with an organ. These abnormalities
Chapter | 1 Introduction
produce physiological symptoms of diseases. Therefore,
drug discovery approaches can be based on mechanism
of action (screening compounds for their effect on a par-
ticular biological target, as discussed above), on function
(screening compounds for their ability to induce or normal-
ize functions, such as growth processes, hormone secre-
tion, or apoptosis (cell death)), or on physiology (screening
compounds in isolated organ systems or in animal models
of disease to reduce symptoms of the disease). The latter
approach, using animal models, was actually the first drug
discovery approach, but it is now generally used as a last
resort because of the low screening capacity, its expense,
and the difficulty to identify the mechanism of action.
1.3.4. Lead Discovery
As noted in Section 1.1, drugs are generally not discovered;
lead compounds are discovered. In the modern drug discov-
ery paradigm that we are discussing, a lead compound typi-
cally has most or all of the following characteristics:
l It interacts with the target in a manner consistent with that
needed to achieve the desired effect.
l It is amenable to synthetic modifications needed to
improve properties.
l It possesses, or can be modified to possess, physical prop-
erties consistent with its ability to reach the target after
administration by a suitable route. For example, evidence
suggests that compounds with a high molecular weight
(>∼500), many freely rotatable bonds, high lipophilic-
ity, and too many hydrogen bond-forming atoms have a
reduced probability of being well absorbed from the gas-
trointestinal tract after oral administration. Therefore, it is
desirable for a lead compound of a drug that is to be admin-
istered orally to either already possess the necessary prop-
erties or be amenable to modification to incorporate them.
Common sources of lead compounds are the following:
l The natural ligand or substrate for the target of interest. For
example, dopamine (1.27) is the natural ligand for the fam-
ily of dopamine receptors. Increasing dopamine concentra-
tions is an important aim for the treatment of Parkinson’s
disease. Therefore, dopamine was the lead compound for
the discovery of rotigotine (1.28), a drug used for the treat-
ment of Parkinson’s disease and restless leg syndrome.[38]
CH3
N S
HO NH2
HO OH
Dopamine Rotigotine
1.27 1.28
11
l Another substance already known to interact with the tar-
get of interest. For example, the plant alkaloid cytisine
(1.29) was known to interact with nicotinic acetylcholine
receptors. Another well-known plant alkaloid, nicotine
(1.30), also interacts with these receptors. Cytisine was
the lead compound used for the Pfizer’s development of
varenicline (1.31, Chantix), a drug that helps patients quit
smoking.[39] Comparing the three structures, one can also
imagine that the structure of nicotine inspired some of the
ideas for the modifications of cytisine on the way to the
discovery of varenicline.
O
N
N
N N NH
N CH3 N
H
Cytisine Nicotine Varenicline
1.29 1.30 1.31
l Random or targeted screening. Screening refers to the
exercise of conducting a biological assay on a large col-
lection of compounds to identify those compounds that
have the desired activity. Initially, these compounds
may bind weakly to the target and are known as hits.
Hits can be considered as predecessors to leads (the
hit to lead process is discussed in Chapter 2, Section
2.1.2.3.5). Assays that rapidly measure binding affini-
ties to targets of interest, called high-throughput
screens, have been commonly used for this purpose
since the early 1990s. Alternatively, cellular responses
that are influenced by the target of interest may be
measured. For example, activation of some receptors,
such as dopamine receptors, is known to result in an
increase in the concentration of Ca2+ ions inside the
cell. Therefore, measurement of changes in the intra-
cellular Ca2+ concentration in cells (with Ca2+-sensitive
dyes) that express dopamine receptors (either naturally
or by transfection) can be used to identify ligands for
these receptors. Such biochemical and cellular methods
have largely supplanted the earlier practice of screen-
ing compounds in whole animals or in sections of tis-
sue. Random screening implies that there is no effort
to bias the set of screened compounds based on prior
knowledge of the target or its known ligands; therefore,
random compounds are screened. Targeted screening
implies application of some prior knowledge to intel-
ligently select compounds that are judged most likely
to interact with the target.
l Fragment-based screening. Several screening methods
using, for example, X-ray crystallography or NMR spec-
trometry have been developed to identify simple mole-
cules (fragments) possessing typically modest affinity for
12
a target, with the intent of connecting two or more of these
fragments to create a useful lead compound (Chapter 2,
Section 2.1.2.3.6).
l Computational approaches. Given knowledge of the
binding site on the target (for example through X-ray
crystallography) or of the structure of several known
ligands, computational approaches may be used to
design potential lead compounds (Chapter 2, Section
2.2.6).
With respect to random screening, a major consider-
ation is the source of the large number of compounds usu-
ally required to identify good leads, and it is an important
role of organic chemists to address this question. For the
targeted approach, the intelligent selection of compounds
to be screened is an additional consideration requiring
the attention of organic and computational chemists. Fur-
ther aspects of these topics will be discussed in detail in
Chapter 2.
1.3.5. Lead Modification (Lead Optimization)
Once one or more lead compounds have been identified,
what more needs to be done before you have a viable drug
candidate? Typically it is necessary, or at least advanta-
geous, to optimize at least one, but more often several, of
a number of key parameters to have the highest probabil-
ity of identifying a successful drug. As discussed in more
detail below, the most notable parameters that may need
to be optimized include: potency; selectivity; absorption,
distribution, metabolism, and excretion (ADME); and intel-
lectual property position. This process normally involves
synthesizing modified versions (analogs) of the lead com-
pound and assessing the new substances against a battery
of relevant tests. It is not uncommon to synthesize and test
hundreds of analogs in the lead optimization process before
a drug candidate (a compound worthy of extensive animal
testing) is identified.
1.3.5.1. Potency
Potency refers to the strength of the biological effect, or put
another way, how much (what concentration) of the com-
pound is required to achieve a defined level of effectiveness.
Thus, all other things being equal, the more potent a drug,
the less will need to be administered to achieve the desired
effect. Administering less drug is desirable from a number
of viewpoints, including minimizing the cost per dose of the
drug and maximizing the convenience of administration,
that is, avoiding overly large pills, a need to take a large
number of pills at the same time, or the necessity to take
the drug more than twice a day. Perhaps more importantly,
if lower doses of the drug can be administered to achieve
a desired effect, then the probability should be lower that
other unintended sites of action (“off-targets”), especially
The Organic Chemistry of Drug Design and Drug Action
those unrelated to the desired target, will be affected, which
can lead to unwanted side effects. Sometimes interactions
with unrelated targets are not detected until they are revealed
in advanced studies involving, for example, chronic admin-
istration in animals or studies in humans. Such late-stage
discoveries can be costly indeed!
1.3.5.2. Selectivity
Unintended sites of action, noted above, refer to interac-
tions with unidentified or unexpected targets. In addition,
there may be off-targets that are related to the intended tar-
get, with which it would be disadvantageous for the drug to
interact. For example, the dopamine D3 receptor discussed
above has related family members, namely, the dopamine
D1, D2, D4, and D5 receptors, all of which utilize dopa-
mine as the endogenous ligand but can mediate different
responses.[40]
There are other well-known off-targets that should be
avoided. One example is the cytochrome P450 (CYP) fam-
ily of enzymes, which are responsible for the metabolism
of many drugs (Chapter 7). Inhibiting a CYP enzyme can
inhibit the metabolism of other drugs that someone may be
taking at the same time, leading to dramatic changes in the
levels of the other drugs. The result, referred to as drug–
drug interactions, can severely limit the drugs that you can
take at the same time or can cause, sometimes, fatal accu-
mulation of other drugs.
Table 1.2 summarizes common targets against which
selectivity would be desirable during lead optimization.
If a lead compound interacts potently with any of these
targets, then assessment of the newly synthesized com-
pounds against the affected target(s) often occurs early
TABLE 1.2 Common “Off-Targets” that should be
Avoided During Lead Modification
Off-Target Role or Reason for Avoiding as Off-Target
Related family Although targets may be related, their actions
members may be quite different from, or even opposed
to, those of the primary target, leading to
­undesired effects
Cytochrome Assist in eliminating drugs from the system.
P450 enzymes Inhibiting these off-targets can result in
drug–drug interactions
Transporters Transporters may be involved in regulating the
extent to which drugs are concentrated inside
vs outside of cells or the extent to which drugs
are absorbed from the intestine. Inhibiting these
off-targets can result in drug–drug interactions
hERG channel Has a role in maintaining proper heart rhythm;
inhibition can lead to fatal arrhythmias
Chapter | 1 Introduction
in the testing process, with the objective of identifying
which structural features are responsible for the undesired
interactions.
1.3.5.3. Absorption, Distribution, Metabolism,
and Excretion (ADME)
Absorption refers to the process by which a drug reaches the
bloodstream from its site of administration. Frequently, the
term is presumed to refer to absorption from the gastroin-
testinal tract after oral administration because this is often
the preferred route of administration. However, it can also
apply to absorption after other routes of administration, for
example, nasal, oral inhalation, vaginal, rectal, subcutane-
ous, or intramuscular administration. In essentially every
case, other than intravenous administration, a drug must
pass through cell membranes on its way to the bloodstream.
In the case of oral administration, a drug entering the blood-
stream is funneled immediately through the liver, where it
may be subject to extensive metabolism (see below) before
passing into the systemic circulation.
Distribution refers to what “compartments” in the body
the drug goes. For example, some drugs stay primarily in
the bloodstream, while others distribute extensively into tis-
sues. Physical properties of the compounds, such as aque-
ous solubility and partition coefficient (a measure of affinity
for organic vs aqueous environment), can have a significant
effect on drug distribution, and therefore are key parame-
ters that are frequently monitored and modified during lead
optimization.
Metabolism refers to the action of specific enzymes on
a drug to convert it to one or more new molecules (called
metabolites). Together with excretion of the intact drug (see
below), metabolism is a major means by which the body
clears a drug from the system. A common overall objective
in drug discovery is to identify a compound for which thera-
peutic (but not toxic) levels in the system can be maintained
following a convenient dosing schedule (for example, once
or twice a day). This may entail identifying a drug that lasts
long enough, but not too long. Therefore, understanding
and controlling the metabolism of a drug are frequently
major objectives of a lead optimization campaign. More-
over, metabolites may themselves be biologically active,
leading in favorable cases to an increase or prolongation
of the desired activity, or in unfavorable cases to undesired
side effects. Chapter 8 discusses the organic chemistry of
metabolic processes, and thereby provides key concepts for
rational approaches to address metabolism issues during
lead optimization.
Excretion refers to means by which the body eliminates
an unchanged drug or its metabolites. The major routes
of excretion are in the urine or feces. Exhalation can be
a minor route of excretion when volatile metabolites are
produced.
13
1.3.5.4. Intellectual Property Position
Discovering a new drug and bringing it to market is an
exceptionally expensive endeavor, with some cost estimates
ranging from $1.2–1.8 billion for each successful drug.[41]
To recover the costs and also be able to appropriately com-
pensate investors who are financing the research (and incen-
tivize potential new investors), it is imperative to obtain a
patent on a drug that is progressing toward drug develop-
ment. The patent gives the patent holder the legal means to
prevent others from making, selling, or importing the drug,
effectively granting the holder a monopoly, for a limited
period of time, on selling the drug. To obtain the most useful
form of a patent, the chemical structure must be novel and
nonobvious compared to publicly available information.
It is within the scope of responsibilities of the medicinal
chemist to conceive and synthesize the substances that meet
the potency, selectivity, and ADME criteria discussed above
while being novel and nonobvious. The successful accom-
plishment of all of those stringent criteria requires innova-
tion, highly creative thinking, and superior synthetic skills.
1.3.6. Drug Development
Drug development normally refers to the process of taking
a compound that has been identified from the drug discov-
ery process described above through the subsequent steps
necessary to bring it to market. Typically, these additional
major steps include preclinical development, clinical devel-
opment, and regulatory approval.
1.3.6.1. Preclinical Development
Preclinical development is the stage of research between
drug discovery and clinical development, which typically
entails:
l Development of synthetic processes that will enable the
compound to be manufactured in reproducible purity on
large (multikilogram) scale.
l Development of a formulation, in most cases a solution
or suspension of the drug that can be administered to ani-
mals in toxicity tests and a solution or suspension or pill
that can be administered to humans in clinical trials.
l Toxicity testing in animals under conditions prescribed
by the regulatory authorities in the region where the clini-
cal trials will occur (the FDA in the US; the European
Medicines Agency in Europe; the Japanese Ministry of
Health and Welfare in Japan).
l Following toxicity studies, gaining permission from the
regulatory authorities to administer the drug to humans.
In the US, such permission is obtained through the sub-
mission to the FDA of an Investigational New Drug
(IND) application, which summarizes the discovery and
preclinical development research done to date.
14
1.3.6.2. Clinical Development (Human Clinical
Trials)
Clinical development is normally conducted in three phases
(Phases I–III) prior to applying for regulatory approval to
market the drug:
l Phase 0 trials, also known as human microdosing stud-
ies, were established in 2006 by the FDA for exploratory,
first-in-human trials.[42] They are designed to speed up
the development of promising drugs or imaging agents
from preclinical (animal) studies. A single subtherapeutic
dose of the drug is administered to about 10–15 healthy
subjects to gather preliminary human ADME data on the
drug and to rank order drug candidates that have similar
potential in preclinical studies with almost no risk of side
effects to the subjects.
l Phase I evaluates the safety, tolerability (dosage levels
and side effects), pharmacokinetic properties, and phar-
macological effects of the drug in about 20–100 indi-
viduals. These individuals are usually healthy volunteers
although actual patients may be used when the disease
is life-threatening. A key objective of these studies is
to attempt to correlate the results of the animal toxicity
studies (including levels of the drug in blood and various
tissues) with findings in humans to help establish the rel-
evance of the animal studies. Phase I generally lasts a few
months to about a year and a half.
l Phase II assesses the effectiveness of the drug, determines
side effects and other safety aspects, and clarifies the dos-
ing regimen in a few hundred diseased patients. These
studies typically provide an initial sense of effectiveness
of the drug against the disease, but, because of the lim-
ited size and other factors, are not generally regarded as
definitive to establish drug efficacy. Phase II typically
lasts from 1 to 3 years.
l Phase III is a larger trial typically with several thousand
patients that establishes the efficacy of the drug, moni-
tors adverse reactions from long-term use, and may com-
pare the drug to similar drugs already on the market.
Appropriate scientific controls are included to allow sta-
tistically meaningful conclusions to be made on the effec-
tiveness of the drug. Phase III typically requires about
2–6 years to be completed.
1.3.6.3. Regulatory Approval to Market
the Drug
In the US, regulatory approval requires submission to the
FDA of a New Drug Application (NDA), summarizing the
results from the clinical trials. This can now be done elec-
tronically; previously, it would require, literally, a truckload
of paper describing all of the preclinical and clinical stud-
ies. On the basis of these data, the FDA decides whether
to grant approval for the drug to be prescribed by doctors
The Organic Chemistry of Drug Design and Drug Action
and sold to patients. Once the drug is on the market, then
it is possible to assess the real safety and tolerability of a
drug because it is taken by hundreds of thousands, if not
millions, of people. Such postmarketing surveillance activi-
ties are often referred to as Phase IV studies because this is
when statistically insignificant effects in clinical trials can
become significant with a large and varied patient popu-
lation, leading to side effects not observed with relatively
small numbers of patients in Phase III trials. On the other
hand, Phase IV studies may reveal new indications for a
drug with patients having symptoms from other diseases.
1.4. EPILOGUE
It should be appreciated from the foregoing discussions
that the drug discovery and development process is a long
and arduous one, taking on average from 12 to 15 years, a
time that has been constant for over 30 years. For approxi-
mately every 20,000 compounds that are evaluated in vitro,
250 will be evaluated in animals, 10 will make it to human
clinical trials, to get one compound on the market at a
cost estimate of $1.2–1.8 billion (in 1962 it was only
$4 million!). Drug candidates (or new chemical entities or
new molecular entities as they are often called) that fail late
in this process result in huge, unrecovered financial losses
for the company. Furthermore, getting a drug on the market
may not be so rewarding; it has been estimated that only
30% of the drugs on the market actually make a profit.[43]
This is why the cost to purchase a drug is so high. It is not
that it costs that much to manufacture that one drug, but
the profits are needed to pay for all of the drugs that fail to
make it onto the market after large sums of research funds
have already been expended or that do not make a profit
once on the market. In addition, funds are needed for future
research efforts. As a result, to minimize expenses, out-
sourcing has become an important economic tool.[44] Not
only are labor rates significantly lower in Eastern Europe
and Asia than in the United States and Western Europe, but
outsourcing also allows a company to have more flexibility
to manage its staffing needs compared to hiring full time
staff. Interestingly, the rise in drug discovery costs has not
been accompanied by a corresponding increase in the num-
ber of new drugs being approved for the market. In 1996,
53 drugs were approved by the FDA, and in 2002, only 16
drugs were approved; 2002 was the first time in the US that
generic drug sales were greater than nongeneric drug sales.
From 2004 to 2010, 20–28 drugs per year were approved
by the FDA,[45] and many of these are just new formula-
tions or minor modifications of existing drugs; in general,
only five or six of the new drugs approved each year are
first-in-class. Possible contributors to this lower-drug-
approval-at-higher-cost trend (other than inflation) include
increasingly higher regulatory hurdles, for example, greater
safety regulations for drug approval, as well as recent efforts
Chapter | 1 Introduction
to tackle increasingly difficult therapeutic objectives, such
as ­curing cancers or halting the progression of Alzheimer’s
disease.[46] In 2011 and 2012 new drug approvals rose to 30
and 39, respectively, suggesting a possible effect of some of
the more modern approaches discussed in this book. Unfor-
tunately, in 2013 that number dropped to 27, indicating we
still have a lot of work to do.
Mechanistic and synthetic organic chemistry play a cen-
tral role in numerous critical aspects of the drug discovery
process, most prominently in generating sufficient numbers
of compounds for lead discovery, in effectively optimiz-
ing compounds for potency, selectivity, and intellectual
property position, and in understanding factors governing
ADME. The ensuing chapters will delve in detail into the
organic chemistry of these critical aspects of drug design
and drug action.
1.5. GENERAL REFERENCES
Journals and Annual Series
ACS Chemical Biology
ACS Medicinal Chemistry Letters
Advances in Medicinal Chemistry
Annual Reports in Medicinal Chemistry
Annual Review of Biochemistry
Annual Review of Medicinal Chemistry
Annual Review of Pharmacology and Toxicology
Biochemical Pharmacology
Biochemistry
Bioorganic and Medicinal Chemistry
Bioorganic and Medicinal Chemistry Letters
Chemical Biology and Drug Design
Chemical Reviews
Chemistry and Biology
ChemMedChem
Current Drug Metabolism
Current Drug Targets
Current Genomics
Current Medicinal Chemistry
Current Opinion in Chemical Biology
Current Opinion in Drug Discovery and Development
Current Opinion in Investigational Drugs
Current Opinion in Therapeutic Patents
Current Pharmaceutical Biotechnology
Current Pharmaceutical Design
Current Protein and Peptide Science
Drug Design and Discovery
Drug Development Research
Drug Discovery and Development
Drug Discovery Today
Drug News and Perspectives
Drugs
Drugs of the Future
15
Drugs of Today
Drugs under Experimental and Clinical Research
Emerging Drugs
Emerging Therapeutic Targets
European Journal of Medicinal Chemistry
Expert Opinion on Drug Discovery
Expert Opinion on Investigational Drugs
Expert Opinion on Pharmacotherapy
Expert Opinion on Therapeutic Patents
Expert Opinion on Therapeutic Targets
Future Medicinal Chemistry
Journal of Biological Chemistry
Journal of Chemical Information and Modeling
Journal of Medicinal Chemistry
Journal of Pharmacology and Experimental Therapeutics
MedChemComm
Medicinal Research Reviews
Methods and Principles in Medicinal Chemistry
Mini Reviews in Medicinal Chemistry
Modern Drug Discovery
Modern Pharmaceutical Design
Molecular Pharmacology
Nature
Nature Chemical Biology
Nature Reviews Drug Discovery
Nature Medicine
Perspectives in Drug Discovery and Design
Proceedings of the National Academy of Sciences
Progress in Drug Research
Progress in Medicinal Chemistry
Science
Science Translational Medicine
Trends in Pharmacological Sciences
Trends in Biochemical Sciences
Books
Abraham, D. J.; Rotella, D. P. (Eds.) Burger’s Medicinal
Chemistry and Drug Discovery, 7th ed., Wiley & Sons,
New York, 2010, Vols. 1–8.
Albert, A. Selective Toxicity, 7th ed., Chapman and Hall,
London, 1985.
Ariëns, E. J. (Ed.) Drug Design, Academic, New York,
1971–1980, Vols. 1–10.
Borchardt, R. T.; Freidinger, R. M.; Sawyer, T. K.
Integration of Pharmaceutical Discovery and
Development: Case Histories, Plenum Press, 1998.
Bruton, L.; Chabner, B.; Knollman, B. (Eds.) Goodman
and Gilman’s The Pharmacological Basis of Therapeutics,
12th ed., McGraw-Hill, New York, 2010.
Kerns, E. H.; Di, L. Drug-like Properties: Concepts,
Structure, Design, and Methods, Elsevier: Amsterdam,
2008.
Lednicer, D. Strategies for Organic Drug Synthesis and
Design, 2nd ed., Wiley, New York, 2009.
16
Lednicer, D. Mitscher, L. A. The Organic Chemistry of
Drug Synthesis, seven-volume set, Wiley, New York,
2008, Vol. 7.
Lemke, T. L.; Williams, D. A.; Roche, V. F.; Zito, S. W.
(Eds.) Foye’s Principles of Medicinal Chemistry, 7th ed.,
Lippincott Williams & Wilkins, Philadelphia, 2012.
O’Neil, M. J. (Ed.) The Merck Index, 14th ed., Merck &
Co., Inc., Whitehouse Station, NJ, 2006.
Taylor, J. B.; Triggle, D. J. (Eds.) Comprehensive
Medicinal Chemistry II, Elsevier, Amsterdam; 2007.
Wermuth, C. G. (Ed.) The Practice of Medicinal
Chemistry, 3rd ed., Academic Press, San Diego, 2009.
Blogs
www.biospace.com
www.genengnews.com
pipeline.corante.com/
www.sciencedaily.com/new/health_medicine
Links
American Chemical Society Division of Medicinal
Chemistry. www.acsmedchem.org
American Chemical Society Division of Organic
Chemistry. www.organicdivision.org
BioChemWeb—Chemical Biology subpage. www.bio-
chemweb.org/chemical.shtml
Broad Institutes ChemBank (small molecule guide for
drug discovery). www.broadinstitute.org/chembank
ChemSpider. www.chemspider.com
ClinicalTrials.gov. www.clinicaltrials.gov
Emolecules. www.emolecules.com
EMBL-EBI European Bioinformatics Institute. www.ebi.
ac.uk
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KinasePro (kinase chemistry). www.Kinasepro.word-
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www.ncbi.nlm.nih.gov/
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gov/pubmed
European Patent Office. www.epo.org
US Patent Office. www.uspto.gov/
Bordwell pKa Table. www.chem.wisc.edu/areas/reich/
pkatable/inde.htm
Protein Data Bank (protein crystal structure database).
www.pdb.org
1.6. PROBLEMS (ANSWERS CAN BE
FOUND IN THE APPENDIX AT THE END
OF THE BOOK)
1. Define the following terms.
a. 
Lead compound
b. 
High-throughput screen
The Organic Chemistry of Drug Design and Drug Action
c. Fragment-based screening
d. Metabolite
e. Transporter
f. Enzyme
g. Absorption
2. Describe ways in which lead compounds are obtained.
3. List some ways that drugs can be discovered without
rational design.
4. Name the noncovalent interactions.
5. What problems are associated with compounds that
have low potency for their target?
6. What problems arise from poor selectivity of com-
pounds for a target?
7. Why is it important to patent your drug?
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 Chapter 2

Lead Discovery and Lead Modification

Chapter Outline
2.1. Lead Discovery 20 2.2.5.1. E lectronic Effects: The Hammett
2.1.1. General Considerations 20 Equation72
2.1.2. Sources of Lead Compounds 20 2.2.5.2. Lipophilicity Effects 74
2.1.2.1. Endogenous Ligands 20 2.2.5.2.1. Importance of Lipophilicity 74
2.1.2.2. Other Known Ligands 23 2.2.5.2.2. Measurement of Lipophilicities 74
2.1.2.3. Screening of Compounds 24 2.2.5.2.3. Computer Automation of log P
2.1.2.3.1. Sources of Compounds for Screening 26 Determination78
2.1.2.3.1.1. Natural Products 26 2.2.5.2.4. Membrane Lipophilicity 79
2.1.2.3.1.2. Medicinal Chemistry Collections 2.2.5.3. Balancing Potency of Ionizable Compounds
and Other “Handcrafted” with Lipophilicity and Oral Bioavailability 79
Compounds27 2.2.5.4. Properties that Influence Ability to Cross
2.1.2.3.1.3. High-Throughput Organic Synthesis 27 the Blood–Brain Barrier 81
2.1.2.3.1.3.1. S olid-Phase Library Synthesis 27 2.2.5.5. Correlation of Lipophilicity with Promiscuity
2.1.2.3.1.3.2. Solution-Phase Library and Toxicity 82
Synthesis30 2.2.6. Computational Methods in Lead Modification 83
2.1.2.3.1.3.3. Evolution of HTOS 31 2.2.6.1. Overview 83
2.1.2.3.2. Drug-Like, Lead-Like, and Other 2.2.6.2. Quantitative Structure–Activity
Desirable Properties of Compounds Relationships (QSARs) 83
for Screening 32 2.2.6.2.1. Historical Overview. Steric Effects:
2.1.2.3.3. Random Screening 36 The Taft Equation and Other Equations 83
2.1.2.3.4. Targeted (or Focused) Screening, 2.2.6.2.2. Methods Used to Correlate
Virtual Screening, and Computational Physicochemical Parameters with
Methods in Lead Discovery 36 Biological Activity 84
2.1.2.3.4.1. Virtual Screening Database 37 2.2.6.2.2.1. H ansch Analysis: A Linear Multiple
2.1.2.3.4.2. Virtual Screening Hypothesis 37 Regression Analysis 84
2.1.2.3.5. Hit-To-Lead Process 43 2.2.6.2.2.2. Manual Stepwise Methods:
2.1.2.3.6. Fragment-based Lead Discovery 45 Topliss Operational Schemes
2.2. Lead Modification 54 and Others 85
2.2.1. Identification of the Active Part: 2.2.6.2.2.3. Batch Selection Methods: Batchwise
The Pharmacophore 55 Topliss Operational Scheme, Cluster
2.2.2. Functional Group Modification 57 Analysis, and Others 87
2.2.3. Structure–Activity Relationships 57 2.2.6.2.2.4. Free and Wilson or de Novo
2.2.4. Structure Modifications to Increase Potency, Method88
Therapeutic Index, and ADME Properties 59 2.2.6.2.2.5. Computational Methods for ADME
2.2.4.1. Homologation 60 Descriptors89
2.2.4.2. Chain Branching 61 2.2.6.3. Scaffold Hopping 89
2.2.4.3. Bioisosterism 62 2.2.6.4. Molecular Graphics-Based Lead
2.2.4.4. Conformational Constraints and Modification90
Ring-Chain Transformations 66 2.2.7. Epilogue 93
2.2.4.5. Peptidomimetics 68 2.3. General References 95
2.2.5. Structure Modifications to Increase Oral 2.4. Problems 102
Bioavailability and Membrane Permeability 72 References106

The Organic Chemistry of Drug Design and Drug Action. http://dx.doi.org/10.1016/B978-0-12-382030-3.00002-7

Copyright © 2014 Elsevier Inc. All rights reserved. 19
20
2.1. LEAD DISCOVERY
2.1.1. General Considerations
As discussed in the drug discovery overview in Chapter 1,
identification of suitable lead compounds provides start-
ing points for lead optimization, during which leads are
modified to achieve requisite potency and selectivity, as
well as absorption, distribution, metabolism, and excretion
(ADME), and intellectual property (patent) position. Given
the hurdles often presented by these multiple and diverse
objectives, identification of the best lead compounds can
be a critical factor to the overall success of a drug discov-
ery program. The approach to lead identification taken in a
given drug discovery program will usually take into account
any known ligand (a smaller molecule that binds to a recep-
tor) for the target. At one extreme, if there are already mar-
keted drugs for a particular target, these may serve as lead
compounds; however, in this case, establishing a suitable
intellectual property position may be the greatest challenge.
On the other hand, whereas the endogenous ligand (the
molecule that binds to a biological target in an organism and
is believed to be responsible for the native activity of the
target) has provided good lead structures for many programs,
the endogenous ligand for a new biological target may not
be well characterized, or the only known ligand may not be
attractive as a lead compound. For example, if an endoge-
nous ligand is a complex molecule that is not readily amena-
ble to synthetic modification or has some other undesirable
properties that are not reasonably addressable, it may not be
attractive as a lead, and other approaches to lead discovery
must be considered. In the next few sections, we will first
provide additional examples of endogenous or other known
ligands as lead compounds to complement the examples
given in Chapter 1, and then we will turn to a more detailed
discussion of alternative approaches to lead discovery.
2.1.2. Sources of Lead Compounds
Lead compounds can be acquired from a variety of sources:
endogenous ligands, e.g., substrates for enzymes and trans-
porters or agonists for receptors; other known ligands, includ-
ing marketed drugs, compounds isolated in drug metabolism
studies, and compounds used in clinical trials; and through
screening of compounds, including natural products and other
chemical libraries, either at random or in a targeted approach.
2.1.2.1. Endogenous Ligands
Rational approaches are important routes to lead discovery.
The first step is to identify the cause for the disease state.
Many diseases, or at least the symptoms of diseases, arise
from an imbalance (either excess or deficiency) of a par-
ticular chemical in the body, from the invasion of a foreign
organism, or from aberrant cell growth. As will be discussed
The Organic Chemistry of Drug Design and Drug Action
in later chapters, the effects of the imbalance can be cor-
rected by antagonism or agonism of a receptor (see Chap-
ter 3) or by inhibition of a particular enzyme (see Chapter
5); interference with deoxyribonucleic acid (DNA) bio-
synthesis or function (see Chapter 6) is another important
approach to treating diseases arising from microorganisms
or aberrant cell growth. Once the relevant biochemical sys-
tem is identified, initial lead compounds become the endog-
enous receptor ligands or enzyme substrates. In Chapter 1,
the example of dopamine as a lead compound for the dis-
covery of rotigotine (1.28) was presented. Dopamine is the
endogenous ligand for dopamine receptors, including the
D3 receptor, which is the target of rotigotine. Dopamine is
one of a number of important neurotransmitters, substances
released by nerve cells (neurons) that interact with receptors
on the surface of nearby neurons to propagate a nerve signal
(Figure 2.1). Endogenous neurotransmitters have served as
lead compounds for many important drugs. Table 2.1 shows
Tyr
TH
Dopa
DA
DA
DA DA DA
autoreceptor transporter
Cocaine
DA
D2 D3–D5
D1
DA = dopamine
ATP
Adenylyl cyclase
cAMP
FIGURE 2.1 Depiction of dopamine (DA) in its role as a neurotransmit-
ter. DA is released by a neuron prior to interacting with dopamine receptors
(D1–D5) on the surface of another nearby neuron. Also shown is the dopa-
mine transporter, which terminates the action of dopamine by transporting the
released neurotransmitter from the synaptic cleft back into the presynaptic neu-
ron. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews
Drug Discovery (Kreek, M. J.; LaForge, K. S.; Butelman, E. Pharmacotherapy
of addictions. Nat. Rev. Drug Discov. 2002, 1, 710–726) Copyright 2002.
Chapter | 2 Lead Discovery and Lead Modification 21

H3 C OH
TABLE 2.1 Examples of Endogenous Neurotransmitter CH2
Ligands That Have Served as Lead Compounds for C CH
H H
Drug Discovery
H H
Endogenous Ligand Marketed Drug O
NH2 H Norgestrel
N CH3 2.1
O
HO
H2N CH3 OH
N
H N C CH
H
Serotonin H
Frovatriptan (antimigraine)

O H H
O H HO
CH3
H3C O CH 3
H3C N N S 17α-Ethynyl estradiol
H3C H 2.2
Acetylcholine Cevemaline (dry mouth treatment)
O
OH OH OH CH3
H
HO NH2 O N O CH3
H H CH3 H
HO F F
Norepinephrine H H
Nebivolol (antihypertensive)
O
2.3a

examples of the drugs that evolved from the structures of CH3 OH

the endogeous neurotransmitters serotonin, acetylcholine,
and norepinephrine.
Hormones are another important class of endogenous
substances that have served as lead compounds for drug
discovery. Like neurotransmitters, hormones are released
from cells and interact with receptors on the surface of other
cells. However, whereas receptors for neurotransmitters
are close to the site of neurotransmitter release, hormone
receptors can be at quite some distance from the site of hor-
mone release, so hormones have to travel to their site of
action through the bloodstream. Steroids are one important
class of hormones; lead compounds for the contraceptives
(+)-norgestrel (2.1, Ovral) and 17α-ethynyl estradiol (2.2,
Activella) were the steroidal hormones progesterone (2.3a)
and 17β-estradiol (2.3b), respectively. The endogenous ste-
roid hormones (2.3a and 2.3b) show weak and short-last-
ing effects, whereas oral contraceptives (2.1 and 2.2) exert
strong progestational activity of long duration.
Peptides constitute another broad class of hormones.
Peptides, like proteins, consist of a sequence of amino acid
residues, but are smaller than proteins (in the range of two
to approximately 100 amino acids). Most peptides have low
stability in plasma as a result of the ubiquitous presence of
peptidases (enzymes that catalyze hydrolysis of peptides into
smaller peptides or constituent amino acids). Moreover, pep-
tides usually cannot be delivered orally because of low perme-
ability across gut membranes (as a result of their charge and
polarity) and because of instability to gut peptidases. However,
incorporation of disulfide bonds to cross-link a peptide can
H
H
H H
HO
2.3b
confer enzymatic stability, e.g., linaclotide (2.4, Linzess) used
to treat bowel diseases. Considerable effort has been devoted
to the goal of using natural peptides as lead compounds for the
discovery of derivatives with improved properties. One suc-
cessful drug that resulted from these endeavors is lanreotide
(2.5, Somatuline),[1] a long-acting analog of the peptide hor-
mone somatostatin (2.6), which is administered by injection
to treat acromegaly (thickening of skin and enlargement of
hands and feet from overproduction of growth hormone).
The discussion of endogenous ligands so far has
focused on leads for drugs designed to interact with recep-
tor targets. Endogenous ligands for other types of drug
targets, including transporters and enzymes, have also
served as valuable starting points for drugs. As mentioned
in Chapter 1, transporters are proteins that help transport
substances across cell membranes. One important class
of transporters is responsible for neurotransmitter reup-
take.[2] As illustrated in Figure 2.1 for the neurotransmit-
ter dopamine, after dopamine is released into the synaptic
cleft, excess neurotransmitter is transported back into the
neuron that released it (the presynaptic neuron) by specific
transporter proteins, which serves to deactivate the signal
22 The Organic Chemistry of Drug Design and Drug Action

OH the transporter ligands, that is, norpinephrine or serotonin.

Paroxetine (2.7, Paxil) is an example of a selective sero-
O O O
H tonin reuptake inhibitor marketed as an antidepressant drug
N
HO N NH with considerable structural resemblance to serotonin (2.8).
O NH H O O Transporters of glucose have recently been targeted for the
S
S S HN NH2 treatment of type 2 diabetes.[3]
HN
HO O
O S N O H
N
NH2 S O
O O H
O O NH2
O O NH
N S O N HO
H H O
OH NH NH
N
H H N
O H
HO F Serotonin
Linaclotide Paroxetine (5-hydroxytryptamine, 5-HT)
2.4 2.7 2.8

Similarly, an important source of leads for the design of

Val-Cys-Thr-NH2
enzyme inhibitors can be the corresponding enzyme sub-
Lys S strate. For example, rivastigmine (2.9, Exelon) is an ace-
tyl cholinesterase inhibitor prescribed as a treatment for
D-Trp
dementia, for which the ultimate starting point was acetyl-
S
choline (Table 2.1), although in actuality, the evolution of
Tyr-Cys-2-Nal-H rivastigmine occurred across several generations of drugs
(you are probably thinking it is hard to see how this struc-
Lanreotide ture could come from acetylcholine, but that is how lead
(Nal = 2-naphthylalanine) optimization evolves new structures).
2.5
CH3 O
Thr-Phe-Thr-Ser-Cys-OH N
H3 C O N CH3
Lys S H CH3 CH3

Trp S Rivastigmine
Phe-Phe-Asn-Lys-Cys-Gly-Ala-H
Somatostatin
2.6
carried by the neurotransmitter. Therefore, an inhibitor of
a neurotransmitter reuptake transporter would have the
effect of prolonging the action of the neurotransmitter.
Cocaine exerts its effects by inhibiting the dopamine reup-
take transporter. Inhibitors of the reuptake transporters for
other important neurotransmitters, such as norepinephrine
and serotonin, comprise important classes of antidepressant
drugs. The leads for many of these reuptake inhibitors were
2.9
Another example of using an enzyme substrate as a
lead for drug discovery is in the design of kinase inhibitors.
Kinases catalyze the transfer of the terminal phosphate group
of adenosine triphosphate (ATP) and related molecules usu-
ally to the hydroxyl group of another molecule (Scheme 2.1),
for example, to the hydroxyl group on the tyrosine residue
of a substrate protein (protein tyrosine kinase). Thus, kinases
have two substrates, ATP (the phosphate donor) and the
phosphate acceptor. Many kinase inhibitors were ultimately
designed based on the structure of ATP, for example, gefitinib
(2.10, Iressa), which is used for the treatment of lung cancer.

NH2 NH2
N N N N
O
O– O– O– O– O–
R-OH + –O O O O N N
Kinase R-O P O– + –O O O N N
P P P P P
O O– O
O O O O O
HO OH HO OH
ATP
SCHEME 2.1 Reaction catalyzed by the kinase class of enzymes. Kinases catalyze the transfer of the terminal phosphate group of ATP or related mol-
ecules acceptor to the group of a substrate, in this case, an alcohol (ROH).
Chapter | 2 Lead Discovery and Lead Modification 23

F delavirdine (2.13, Rescriptor) was found to antagonize the

histamine H4 receptor, which is a target for the potential treat-
O HN Cl ment of asthma and allergies. Isradipine (2.14, Dynacirc), an
N O antihypertensive drug, is in clinical trials as a treatment for
N
Parkinson’s disease.[7] The antidepressant drug duloxetine
O N (2.15, Cymbalta) has been approved to treat chronic lower
Gefitinib back pain.[8] A common dilemma to the repurposing of mar-
2.10 keted drugs is that if the repurposed drug is used directly for a
new indication, then only a new method of use patent (a patent
Currently, rational approaches to drug discovery are that covers the new use for the molecule) application can be
most relevant to the earlier stages of the process, most filed; however, it is best to own the rights to a molecule for
notably including target identification, lead discovery, and any purpose (composition of matter patent), which an altered
optimization of molecular interactions with the target dur- structure would allow. Therefore, using a known drug as a lead
ing lead optimization. Later stages of drug discovery pres- to discover a novel compound could warrant independent pat-
ently remain much more empirical owing to the difficulties ent protection for the new structure. An important advantage
in accurately predicting toxicities, anticipating transport to repurposed drugs is that whereas only 10% of new drugs
properties, accurately predicting the full range of ADME in Phase I clinical trials and 50% of Phase III drugs make it
properties of a drug, and numerous other factors. However, to the market, the rates for repurposed drugs are 25 and 65%,
active ongoing research is attempting to increase the degree respectively.
of rationality even for these complex facets of drug behav-
ior. In addition to rational approaches, particularly when NH2
N HO
no target protein is known or little structural information is HO N
available for rational design, other less rational approaches
HNaO3P PO3NaH
can be taken to get a starting point for lead discovery using H 2O 3P PO3H2
other known ligands or screening approaches. Zoledronic acid Pamidronate disodium
2.11 2.12
2.1.2.2. Other Known Ligands
O H
In Chapter 1, the example of using the plant alkaloid cyti- N O
S
sine (1.29) as the starting point for discovery of the smoking O
cessation agent varenicline (1.31, Chantix) was described. CH3 N N
H
Another variant of using a known ligand as a starting point is
the use of an established drug as a lead toward development N
of the next generation of compounds.[4] One example is diaz- N
epam (1.17, Valium), as described in Chapter 1, Section 1.2.3, HN
Delavirdine
which was derived from the marketed drug Librium (1.13) 2.13
and is almost 10 times more potent than the lead. Another
example is zoledronic acid (2.11, Zometa), which is used to N
treat osteoporosis (loss of bone density) and hypercalcemia, S H
O
N
a condition resulting in high blood calcium levels due to can- N
cer, and to delay bone complications resulting from multiple Me2CHCO2 O
CO2Me
myeloma and bone metastases. This is a second-generation
drug derived from pamidronate disodium (2.12, Aredia), also Me
Me N
used for treating hypercalcemia from malignancy. H
Known drugs can also be repurposed (the identification Isradipine Duloxetine
and development of new uses for existing or abandoned drugs; 2.14 2.15
also called repositioned) for a completely different indica-
tion.[5] The advantage of a repurposed drug is that the cost Other sources of lead compounds, as described in Chap-
to bring it to market is diminished because the safety and ter 1, Sections 1.2.4 and 1.2.5, are metabolism studies and
pharmacokinetic profiles have already been established for clinical trials. The cases cited in those sections involved
its original indication. A library (a collection of compounds) the identification of new drugs from metabolism or from
of 3665 Food and Drug Administration (FDA)-approved and the clinic, some with novel indications; however, it is pos-
investigational drugs was tested for activity against hundreds sible that the metabolite from a drug metabolism study or a
of targets, from which 23 new drug–target relationships were compound in a clinical trial might act as a lead compound
confirmed.[6] For example, the reverse transcriptase inhibi- for a new indication requiring modification to enhance its
tor and acquired immune deficiency syndrome (AIDS) drug potency or diminish undesirable properties.
24 The Organic Chemistry of Drug Design and Drug Action

2.1.2.3. Screening of Compounds formation of the bacterial cell wall) and also which enzyme
was blocked (the buildup of an intermediate meant that the
Endogenous or other ligands may not be known for a target of
enzyme that acted on that intermediate was blocked).
interest. Alternatively, known ligands for a target may not be
Compound screening also can be carried out by electro-
well suited as starting points for discovery of drugs that will
spray ionization mass spectrometry (MS)[10] (the technique
ultimately possess the desired properties. For example, many
for which John Fenn received the Nobel Prize in 2002) and by
endogenous ligands are large proteins, which are not usually
nuclear magnetic resonance (NMR) spectrometry (the tech-
good leads when the goal is to discover an orally adminis-
nique for which Richard Ernst and Kurt Wüthrich received
tered drug. For these reasons, screening for leads has played
Nobel Prizes in 1991 and 2002, respectively).[11] Tightly
a central role in drug discovery for decades, although techno-
bound noncovalent complexes of compounds with a mac-
logical advances in the past 20 years have markedly changed
romolecule (such as a receptor or enzyme) can be observed
how these screens are conducted, as discussed below.
in the mass spectrum. The affinity of the ligand can be mea-
The first requirement for a screening approach is to have
sured by varying the collision energy and determining at what
a means to assay compounds for a particular biological
energy the complex dissociates. This method also can be used
activity, so that researchers will know when a compound
to screen mixtures of compounds, provided they have dif-
is active. Bioassay (or screen) is a means of determining
ferent molecular masses and/or charges, so that m/z for each
in a biological system, relative to a control compound, if
complex with the biomolecule can be separated in the mass
a compound has the desired activity, and if so, what the
spectrometer. By varying the collision energy, it is possible to
relative potency of the compound is. Note the distinction
determine which test molecules bind to the biomolecule best.
between the terms activity and potency. Activity is the par-
The 1H NMR method exploits changes in either relaxation
ticular biological or pharmacological effect (for example,
rates or diffusion rates of small molecules when they bind to a
antibacterial activity or anticonvulsant activity); potency is
macromolecule. This method can also be used to screen mix-
the strength of that effect.
tures of compounds to determine the ones that bind best.
Until the late 1980s many screening efforts were conducted
High-throughput screening (HTS),[12] from which greater
using whole animals or whole organisms, for example, screen-
than two-thirds of drug discovery projects now originate,[13]
ing for antiepileptic activity by assessing the ability of a com-
was initially developed in the late 1980s employing very
pound to prevent an induced seizure in a mouse or rat, or for
rapid and sensitive in vitro screens, which could be carried
antibacterial activity by measuring the effect of test compounds
out robotically. According to Drews,[14] the number of com-
on the growth of bacterial cultures in glass dishes. Especially
pounds assayed in a large pharmaceutical company in the
when screening in whole animals, efforts have often been ham-
early 1990s was about 200,000 a year, which rose to 5–6 mil-
pered by the comparatively large quantities of test compound
lion during the mid-1990s, and by the end of the 1990s it was
required and by the fact that the results depended on other fac-
>50 million! HTS can be carried out robotically in 1536- or
tors apart from the inherent potency of the compound at its
3456-well titer plates on small (submicrogram) amounts of
intended target (pharmacodynamics), for example, the ability
compound (dissolved in submicroliter volumes). With these
of the compound to be absorbed, distributed, metabolized, and
ultrahigh throughput screening approaches of the early part
excreted (pharmacokinetics). Thus, in general, in vitro tests
of the twenty-first century,[15] it is possible to screen 100,000
have fewer confounding factors and are also quicker and less
compounds in a day! In 2010, an HTS method using drop-
expensive to perform. The downside to this approach, however,
based microfluidics (the ability to manipulate tiny volumes
is that you may identify a very potent compound for a target,
of liquid) was reported that allowed a 1000 times faster
but it may not have the ability to be absorbed or is rapidly
screening (10 million reactions per hour) with 10−7 times the
metabolized. This more rapid screening method then requires
reagent volume and at one-millionth the cost of conventional
additional studies of pharmacokinetics once the appropriate
techniques.[16] In this technique, drops of aqueous fluid
pharmacodynamics has been established. Pharmacokinetic
dispersed in fluorocarbon oil replace the microtiter plates,
aspects are discussed further throughout the chapter.
which allows analysis and compound sorting in picoliter
An exciting approach for screening compounds that might
volume reactions while reagents flow through channels. A
interact with an enzyme in a metabolic pathway was demon-
silicone sheet of lenses can be used to cover the microfluidic
strated by Wong, Pompliano, and coworkers for the discovery
arrays, allowing fluorescence measurements of 62 differ-
of lead compounds that block bacterial cell wall biosynthesis
ent output channels simultaneously and analysis of 200,000
(as potential antibacterial agents).[9] ­Conditions were found
drops per second.[17] Therefore, screening compounds is no
to reconstitute all six enzymes in the cell wall biosynthetic
longer the slow step in the lead discovery process!
pathway so that incubation with the substrate for the first
Because of the ease of screening vast numbers of com-
enzyme led to the formation of the product of the last enzyme
pounds, early in the application of HTS, every compound
in the pathway. Then by screening compounds and looking
in the company library, regardless of its properties, was
for the buildup of an intermediate it was possible to identify
screened. By the early part of the first decade of the twenty-
compounds that blocked the pathway (and prevented the
first century, because an increase in the number of useful
Chapter | 2 Lead Discovery and Lead Modification 25

lead compounds was not forthcoming despite the huge rise
in the application of screening, it was realized that the physi-
cochemical properties of molecules were key for screen-
ing compounds.[18] Therefore, additional considerations for
HTS became the sources and selection of compounds to be
screened and the development of effective methods for pro-
cessing and utilizing the screening data that were generated.
Medicinal chemists have an important role in these activities,
which we discuss in more detail in the next several sections.
A keyword search for “high-throughput screening” in the
Journal of Medicinal Chemistry website (http://pubs.acs.org/
journal/jmcmar) readily retrieves a multitude of examples
in which HTS played a central role in lead discovery. Rep-
resentative examples are shown in Table 2.2, together with

TABLE 2.2 Examples of Hits from HTS and Analogs Resulting from Subsequent Optimization Efforts

Biological Target HTS Hit Representative Structure after Initial or Full Optimization
Peroxisome CH3
proliferator-­ HO2C
S N
activated OCH3
S
receptor (PPAR)
δ (target class:
nuclear hor-
mone OCH3
receptor)
EC50 = 3200 nM

EC50 = 17 nM

Rho kinase
(target class:
enzyme)

IC50 = 2300 nM

IC50 = 4 nM

KCNQ2/Q3
potassium chan-
nels (target class:
ion channel)

EC50 = 27 nM EC50 = 49 nM
Significantly increased oral efficacy

Influenza A CH3
(H1N1) virus

O O O

S O
IC50 = 4500 nM IC50 = 70 nM

Vascular endo- CH3

thelial growth
factor receptor 2 N
N CH3
kinase domain N
HN N N
(target class:
enzyme) CH3

IC50 ∼ 400 nM SO2NH2

CH3
IC50 = 30 nM
Marketed drug (pazopanib)
26
structures of products from subsequent lead optimization
activities.[19] See Section 2.2 for what properties need to be
considered prior to and during the lead optimization process.
2.1.2.3.1. Sources of Compounds for Screening
As stated above, besides a high-throughput assay, an essential
second requirement for HTS is a large number of suitable
compounds for screening. In the following several subsec-
tions, we discuss the most common sources of compounds
for HTS. The criteria for selecting compounds to be added to
a general screening collection and for improving the selection
of specific compounds for a given screen have evolved con-
siderably over the past decade. An important goal of an orga-
nization that conducts many HTS campaigns across a variety
of types of biological targets will be to construct a screening
library of structurally diverse compounds. The assumption is
that structurally similar compounds will have similar biologi-
cal activities, and conversely, that structurally diverse collec-
tions will show divergent biological activities. In general, this
is the case; however, such generalizations should be made
with caution, since Dixon and Villar showed that a protein
can bind a set of structurally diverse molecules with similar
potent binding affinities, and analogs closely related to these
compounds can exhibit very weak binding.[20]
TABLE 2.3 Examples of Natural Product Lead Compounds and Marketed Drugs Derived from Them
Natural Product Lead Compound
Echinocandin B (a fungal metabolite)
Epothilone B (from bacterial fermentation)
The Organic Chemistry of Drug Design and Drug Action
2.1.2.3.1.1. Natural Products Nature is still an excellent
source of drug precursors, or in some cases, of actual drugs.
Although endogenous ligands discussed earlier are technically
also natural products, the present category is intended to
encompass products from nonmammalian natural sources,
for example, plants, marine organisms, bacteria, and fungi.
Nearly half of the new drugs approved between 1994 and 2007
are based on natural products, including 13 natural product-
related drugs approved from 2005 to 2007.[21] More than 60%
of the anticancer and antiinfective agents that went on the
market between 1981 and 2006 were of natural product origin
or derived from natural products; if biologicals, for example,
antibodies and genetically engineered proteins, and vaccines
are ignored, then the percentage increases to 73%.[22] This may
be a result of the inherent nature of these secondary metabolites
as a means of defense for their producing organisms; for
example, a fungal natural product that inhibits cell replication
may be produced by the fungus to act on potential invading
organisms such as bacteria or other fungi.[23] Table 2.3 shows
two examples of recently approved drugs that were derived
from natural product lead compounds[24]; many others are
currently in various stages of clinical development.
It has been suggested that small molecule natural prod-
ucts tend to target essential proteins of genes from organisms
Marketed Drug
HO OH
O
HO O O
NH NH
CH3
N O
O HN OH
CH3
NH O CH3
HO H
N N
O
OH
HO
OH O
HO
Anidulafungin (antifungal)
Ixabepilone (anti-cancer)
Chapter | 2 Lead Discovery and Lead Modification
with which they coevolved, rather than those involved in
human disease, and the reverse is true of synthetic drugs.[25]
According to this hypothesis, natural products should be
important molecules to combat microorganisms or aberrant
(tumor) cell growth, but they should not be expected to be
effective for other diseases, such as central nervous system
(CNS) or cardiovascular diseases. However, genomes and
biological pathways can be conserved across a variety of
organisms. Furthermore, evolution over billions of years has
produced these natural products to bind to specific regions
in targets, and these binding regions can be very similar in
targets for human disease as well as in microorganisms.
Because natural products often have the ability to cross
biological barriers and penetrate cells, they often have desir-
able pharmacokinetic properties, which makes them good
starting points for lead discovery. In fact, several structural
neighbors of active natural products were shown to retain
the same activity as the natural product.[26] One measure of
the potential oral bioavailability of a compound is a set of
guidelines called the Rule of 5 (see Section 2.1.2.3.2). About
60% of the 126,140 natural products in the Dictionary of
Natural Products had no violations of these guidelines, and
many natural products remain bioavailable despite violating
these rules.[27] This supports natural products as being an
important source of lead compounds.
Frequently, screening of natural products has been done
on semipurified extracts of sources such as plant materi-
als, marine organisms, or fermentation broths. A significant
challenge in screening of natural products in this way is
that when activity is found, there is still considerable work
to be done to isolate the active component and determine
its structure. When HTS of chemical libraries started, such
slower, more tedious screening methods were often put
aside. However, because of the earlier success with natural
product screening, the natural product approach has begun
to return to the drug discovery process.
2.1.2.3.1.2. Medicinal Chemistry Collections and Other
“Handcrafted” Compounds Many large, established
pharmaceutical companies have been synthesizing
compounds in one-at-a-time fashion for decades as part
of their overall drug discovery efforts. In most cases, these
institutions have had long-standing compound inventory
management systems, such that samples of compounds
prepared many years ago are still available for screening. One
advantage of using these compounds for screening is that they
are frequently close analogs of compounds that progressed
substantially through the drug discovery process and thus
have a reasonable probability of possessing biological activity
and drug-like properties. One disadvantage, though, is that
these compounds may be structurally biased toward the
limited proteins that these companies have targeted over the
years. Large companies may possess up to several million
compounds in their corporate compound collections; however,
most companies have substantially trimmed their collections
27
used for screening, leaving only compounds that have good
drug-like properties for lead discovery (see Section 2.1.2.3.2).
Another source of handcrafted compounds is samples
from academic or nonpharmaceutical synthetic laboratories.
Some businesses have been established to purchase such
samples and market them to drug discovery organizations.
2.1.2.3.1.3. High-Throughput Organic Synthesis To
provide the large number of compounds needed to feed
ultrahigh throughput screening operations, enormous efforts
during the 1990s turned toward developing methods for
high-throughput organic synthesis (HTOS). HTOS had its
origins in the techniques of solid-phase synthesis (synthesis
carried out on a polymer support, which makes removal of
excess reagents and by-products from the desired product
easier), and many drug discovery organizations established
internal HTOS groups to supply compounds for screening
using solid-phase chemistry. Millions of compounds were
synthesized for HTS campaigns using these HTOS methods.
The synthesis of large numbers of related compounds has
now declined substantially in favor of smaller sets,[28] and
this evolution has been accompanied by a dramatic shift of
emphasis from solid-phase methods back to solution-phase
chemistry. One approach taken to create more diversity in
chemical libraries called diversity-oriented synthesis, the
synthesis of numerous diverse scaffolds from a common
intermediate, has had limited success.[29] Below we briefly
review key aspects of the HTOS approach of the 1990s and
early 2000s and its relationship to HTS during these years,
because some of the lessons learned during this period serve
as key concepts in the present practices of lead discovery.
2.1.2.3.1.3.1. Solid-Phase Library Synthesis The most widely
practiced methods in the early application of HTOS centered
on the simultaneous synthesis of large collections (libraries)
of compounds using solid-phase synthesis techniques. The
synthesis of large numbers of compounds generally relied on a
combinatorial strategy, that is, the practice of combining each
member of one set of building blocks (i.e., reactants) with
each member of one or more additional sets of building blocks
(see examples below).[30] The beginnings of combinatorial
chemistry are attributed to Furka,[31] with applications
in peptide synthesis by Geysen and coworkers[32] and by
Houghten.[33] These initial efforts in peptide library synthesis
were followed by the synthesis of peptoids by Zuckermann
and coworkers[34] and of small molecule nonpeptide libraries
by Ellman and coworkers[35] and Terrett and coworkers.[36]
The efficiency of HTOS in producing large numbers
of compounds relies, among other factors, on the ability to
conduct reactions on multiple different (albeit often related)
reactants in parallel. Solid-phase synthesis[37] is carried out
by covalently attaching the starting material to a polymeric
solid support and conducting a sequence of reactions while
the corresponding intermediates and product remain attached
to the solid phase, ultimately followed by a cleavage step to
release the product into solution. Classically, functionalized
28 The Organic Chemistry of Drug Design and Drug Action

polystyrene beads (polystyrene resin) were used as the solid
support, although many other polymeric materials have since
been developed expressly for the purpose of increasing the
versatility of the solid-phase methodology. To minimize
unreacted starting material, excess reagents are usually used,
which are then easily removed along with any solution-phase
by-products by filtration and repeated washing of the solid-
phase material. This type of reaction workup is well suited to
parallel processing and automation, accounting for its initial
broad implementation for synthesis of large libraries. Some-
what less well advertised during the early hype of solid-phase
combinatorial chemistry was the fact that side reactions can
and do occur during solid-phase synthesis just as they do in
solution, and the resulting polymer-bound side products are
retained as impurities throughout the solid-phase process.
Monitoring reactions on solid phase is not as straightforward
as it is for solution-phase reactions; it requires either special-
ized methods such as Fourier transform infrared spectroscopy
or separate cleavage of an aliquot of a polymer-bound inter-
mediate to release it into solution so it can be analyzed by
conventional methods such as thin-layer chromatography or
high-performance liquid chromatography (HPLC). Neverthe-
less, since the early days of solid-phase peptide synthesis (the
Merrifield synthesis[38]) carried out through sequential amide
couplings and amine deprotections, a remarkably wide vari-
ety of reactions have been adapted to solid-phase methods.[39]
An early example of using solid-phase methodology
to synthesize a nonpeptide library was the preparation of
benzodiazepines as shown in Scheme 2.2.[40] Key reactions
on solid phase include a Stille coupling to form ketone
2.18, an amide coupling followed by an N-deprotection to
form aminoketone 2.20 (note that by-products from Fmoc
cleavage are soluble and thus readily removed), acid-pro-
moted intramolecular imine formation to give polymer-
bound benzodiazepine 2.21, and an N-alkylation to form
the polymer-bound version (2.23) of the final product.
The p-alkoxybenzyl linker 2.16 serves two purposes: (1)
the p-alkoxyl substituent promotes the release of the final
product from the polymer under acid conditions and (2) it
acts as a spacer, moving the sites of the reactions in the syn-
thetic sequence away from the surface of the resin to avoid
steric hindrance to reaction and to facilitate access to the
reaction sites by reactants in solution. In this solid-phase
synthesis, there are three diversity elements (R1, R2, and
R3), which are correspondingly introduced by three sets of
building blocks (also known as monomers), namely, a set
of acid chlorides 2.17, a set of Fmoc-protected amino acids
2.19, and a set of alkylating agents 2.22. The theoretical

NHBpoc
O O NHBpoc
NC PPh3 NC O O
OH + O SnMe3
HO SnMe3 DEAD
O O
2.16 O
Bpoc = C OC NH2
H3C CH3
R2
NHBpoc
1. FmocNH CF NH2
1. Pd2dba3 CHCl3 HN O
2.19 O O
HN O SnMe3
O O iPr2EtN
RlCOCl 2.17 O
2. O Rl
N 2.18 2. CH2Cl2/TFA
piperidine R2
H H
N N O
NH2
HN O O AcOH HN R2
O O
O O N
O Rl O Rl
2.20 2.21
Li
1. N
O
Ph O
2. R3—X
2.22
R3
R3
O N O
N
TFA / Me2S/ H2O R2
R2 HN O
O N
HO N
l O Rl
R
2.23
SCHEME 2.2 Solid-phase synthesis of a library of 7-hydroxybenzodiazepines
Another random document with
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 DANCE ON STILTS AT THE GIRLS’ UNYAGO, NIUCHI

Newala, too, suffers from the distance of its water-supply—at least

the Newala of to-day does; there was once another Newala in a lovely
valley at the foot of the plateau. I visited it and found scarcely a trace
of houses, only a Christian cemetery, with the graves of several
missionaries and their converts, remaining as a monument of its
former glories. But the surroundings are wonderfully beautiful. A
thick grove of splendid mango-trees closes in the weather-worn
crosses and headstones; behind them, combining the useful and the
agreeable, is a whole plantation of lemon-trees covered with ripe
fruit; not the small African kind, but a much larger and also juicier
imported variety, which drops into the hands of the passing traveller,
without calling for any exertion on his part. Old Newala is now under
the jurisdiction of the native pastor, Daudi, at Chingulungulu, who,
as I am on very friendly terms with him, allows me, as a matter of
course, the use of this lemon-grove during my stay at Newala.
 FEET MUTILATED BY THE RAVAGES OF THE “JIGGER”
(Sarcopsylla penetrans)

The water-supply of New Newala is in the bottom of the valley,

some 1,600 feet lower down. The way is not only long and fatiguing,
but the water, when we get it, is thoroughly bad. We are suffering not
only from this, but from the fact that the arrangements at Newala are
nothing short of luxurious. We have a separate kitchen—a hut built
against the boma palisade on the right of the baraza, the interior of
which is not visible from our usual position. Our two cooks were not
long in finding this out, and they consequently do—or rather neglect
to do—what they please. In any case they do not seem to be very
particular about the boiling of our drinking-water—at least I can
attribute to no other cause certain attacks of a dysenteric nature,
from which both Knudsen and I have suffered for some time. If a
man like Omari has to be left unwatched for a moment, he is capable
of anything. Besides this complaint, we are inconvenienced by the
state of our nails, which have become as hard as glass, and crack on
the slightest provocation, and I have the additional infliction of
pimples all over me. As if all this were not enough, we have also, for
the last week been waging war against the jigger, who has found his
Eldorado in the hot sand of the Makonde plateau. Our men are seen
all day long—whenever their chronic colds and the dysentery likewise
raging among them permit—occupied in removing this scourge of
Africa from their feet and trying to prevent the disastrous
consequences of its presence. It is quite common to see natives of
this place with one or two toes missing; many have lost all their toes,
or even the whole front part of the foot, so that a well-formed leg
ends in a shapeless stump. These ravages are caused by the female of
Sarcopsylla penetrans, which bores its way under the skin and there
develops an egg-sac the size of a pea. In all books on the subject, it is
stated that one’s attention is called to the presence of this parasite by
an intolerable itching. This agrees very well with my experience, so
far as the softer parts of the sole, the spaces between and under the
toes, and the side of the foot are concerned, but if the creature
penetrates through the harder parts of the heel or ball of the foot, it
may escape even the most careful search till it has reached maturity.
Then there is no time to be lost, if the horrible ulceration, of which
we see cases by the dozen every day, is to be prevented. It is much
easier, by the way, to discover the insect on the white skin of a
European than on that of a native, on which the dark speck scarcely
shows. The four or five jiggers which, in spite of the fact that I
constantly wore high laced boots, chose my feet to settle in, were
taken out for me by the all-accomplished Knudsen, after which I
thought it advisable to wash out the cavities with corrosive
sublimate. The natives have a different sort of disinfectant—they fill
the hole with scraped roots. In a tiny Makua village on the slope of
the plateau south of Newala, we saw an old woman who had filled all
the spaces under her toe-nails with powdered roots by way of
prophylactic treatment. What will be the result, if any, who can say?
The rest of the many trifling ills which trouble our existence are
really more comic than serious. In the absence of anything else to
smoke, Knudsen and I at last opened a box of cigars procured from
the Indian store-keeper at Lindi, and tried them, with the most
distressing results. Whether they contain opium or some other
narcotic, neither of us can say, but after the tenth puff we were both
“off,” three-quarters stupefied and unspeakably wretched. Slowly we
recovered—and what happened next? Half-an-hour later we were
once more smoking these poisonous concoctions—so insatiable is the
craving for tobacco in the tropics.
Even my present attacks of fever scarcely deserve to be taken
seriously. I have had no less than three here at Newala, all of which
have run their course in an incredibly short time. In the early
afternoon, I am busy with my old natives, asking questions and
making notes. The strong midday coffee has stimulated my spirits to
an extraordinary degree, the brain is active and vigorous, and work
progresses rapidly, while a pleasant warmth pervades the whole
body. Suddenly this gives place to a violent chill, forcing me to put on
my overcoat, though it is only half-past three and the afternoon sun
is at its hottest. Now the brain no longer works with such acuteness
and logical precision; more especially does it fail me in trying to
establish the syntax of the difficult Makua language on which I have
ventured, as if I had not enough to do without it. Under the
circumstances it seems advisable to take my temperature, and I do
so, to save trouble, without leaving my seat, and while going on with
my work. On examination, I find it to be 101·48°. My tutors are
abruptly dismissed and my bed set up in the baraza; a few minutes
later I am in it and treating myself internally with hot water and
lemon-juice.
Three hours later, the thermometer marks nearly 104°, and I make
them carry me back into the tent, bed and all, as I am now perspiring
heavily, and exposure to the cold wind just beginning to blow might
mean a fatal chill. I lie still for a little while, and then find, to my
great relief, that the temperature is not rising, but rather falling. This
is about 7.30 p.m. At 8 p.m. I find, to my unbounded astonishment,
that it has fallen below 98·6°, and I feel perfectly well. I read for an
hour or two, and could very well enjoy a smoke, if I had the
wherewithal—Indian cigars being out of the question.
Having no medical training, I am at a loss to account for this state
of things. It is impossible that these transitory attacks of high fever
should be malarial; it seems more probable that they are due to a
kind of sunstroke. On consulting my note-book, I become more and
more inclined to think this is the case, for these attacks regularly
follow extreme fatigue and long exposure to strong sunshine. They at
least have the advantage of being only short interruptions to my
work, as on the following morning I am always quite fresh and fit.
My treasure of a cook is suffering from an enormous hydrocele which
makes it difficult for him to get up, and Moritz is obliged to keep in
the dark on account of his inflamed eyes. Knudsen’s cook, a raw boy
from somewhere in the bush, knows still less of cooking than Omari;
consequently Nils Knudsen himself has been promoted to the vacant
post. Finding that we had come to the end of our supplies, he began
by sending to Chingulungulu for the four sucking-pigs which we had
bought from Matola and temporarily left in his charge; and when
they came up, neatly packed in a large crate, he callously slaughtered
the biggest of them. The first joint we were thoughtless enough to
entrust for roasting to Knudsen’s mshenzi cook, and it was
consequently uneatable; but we made the rest of the animal into a
jelly which we ate with great relish after weeks of underfeeding,
consuming incredible helpings of it at both midday and evening
meals. The only drawback is a certain want of variety in the tinned
vegetables. Dr. Jäger, to whom the Geographical Commission
entrusted the provisioning of the expeditions—mine as well as his
own—because he had more time on his hands than the rest of us,
seems to have laid in a huge stock of Teltow turnips,[46] an article of
food which is all very well for occasional use, but which quickly palls
when set before one every day; and we seem to have no other tins
left. There is no help for it—we must put up with the turnips; but I
am certain that, once I am home again, I shall not touch them for ten
years to come.
Amid all these minor evils, which, after all, go to make up the
genuine flavour of Africa, there is at least one cheering touch:
Knudsen has, with the dexterity of a skilled mechanic, repaired my 9
× 12 cm. camera, at least so far that I can use it with a little care.
How, in the absence of finger-nails, he was able to accomplish such a
ticklish piece of work, having no tool but a clumsy screw-driver for
taking to pieces and putting together again the complicated
mechanism of the instantaneous shutter, is still a mystery to me; but
he did it successfully. The loss of his finger-nails shows him in a light
contrasting curiously enough with the intelligence evinced by the
above operation; though, after all, it is scarcely surprising after his
ten years’ residence in the bush. One day, at Lindi, he had occasion
to wash a dog, which must have been in need of very thorough
cleansing, for the bottle handed to our friend for the purpose had an
extremely strong smell. Having performed his task in the most
conscientious manner, he perceived with some surprise that the dog
did not appear much the better for it, and was further surprised by
finding his own nails ulcerating away in the course of the next few
days. “How was I to know that carbolic acid has to be diluted?” he
mutters indignantly, from time to time, with a troubled gaze at his
mutilated finger-tips.
 Since we came to Newala we have been making excursions in all
directions through the surrounding country, in accordance with old
habit, and also because the akida Sefu did not get together the tribal
elders from whom I wanted information so speedily as he had
promised. There is, however, no harm done, as, even if seen only
from the outside, the country and people are interesting enough.
The Makonde plateau is like a large rectangular table rounded off
at the corners. Measured from the Indian Ocean to Newala, it is
about seventy-five miles long, and between the Rovuma and the
Lukuledi it averages fifty miles in breadth, so that its superficial area
is about two-thirds of that of the kingdom of Saxony. The surface,
however, is not level, but uniformly inclined from its south-western
edge to the ocean. From the upper edge, on which Newala lies, the
eye ranges for many miles east and north-east, without encountering
any obstacle, over the Makonde bush. It is a green sea, from which
here and there thick clouds of smoke rise, to show that it, too, is
inhabited by men who carry on their tillage like so many other
primitive peoples, by cutting down and burning the bush, and
manuring with the ashes. Even in the radiant light of a tropical day
such a fire is a grand sight.
Much less effective is the impression produced just now by the
great western plain as seen from the edge of the plateau. As often as
time permits, I stroll along this edge, sometimes in one direction,
sometimes in another, in the hope of finding the air clear enough to
let me enjoy the view; but I have always been disappointed.
Wherever one looks, clouds of smoke rise from the burning bush,
and the air is full of smoke and vapour. It is a pity, for under more
favourable circumstances the panorama of the whole country up to
the distant Majeje hills must be truly magnificent. It is of little use
taking photographs now, and an outline sketch gives a very poor idea
of the scenery. In one of these excursions I went out of my way to
make a personal attempt on the Makonde bush. The present edge of
the plateau is the result of a far-reaching process of destruction
through erosion and denudation. The Makonde strata are
everywhere cut into by ravines, which, though short, are hundreds of
yards in depth. In consequence of the loose stratification of these
beds, not only are the walls of these ravines nearly vertical, but their
upper end is closed by an equally steep escarpment, so that the
western edge of the Makonde plateau is hemmed in by a series of
deep, basin-like valleys. In order to get from one side of such a ravine
to the other, I cut my way through the bush with a dozen of my men.
It was a very open part, with more grass than scrub, but even so the
short stretch of less than two hundred yards was very hard work; at
the end of it the men’s calicoes were in rags and they themselves
bleeding from hundreds of scratches, while even our strong khaki
suits had not escaped scatheless.

NATIVE PATH THROUGH THE MAKONDE BUSH, NEAR

MAHUTA

I see increasing reason to believe that the view formed some time
back as to the origin of the Makonde bush is the correct one. I have
no doubt that it is not a natural product, but the result of human
occupation. Those parts of the high country where man—as a very
slight amount of practice enables the eye to perceive at once—has not
yet penetrated with axe and hoe, are still occupied by a splendid
timber forest quite able to sustain a comparison with our mixed
forests in Germany. But wherever man has once built his hut or tilled
his field, this horrible bush springs up. Every phase of this process
may be seen in the course of a couple of hours’ walk along the main
road. From the bush to right or left, one hears the sound of the axe—
not from one spot only, but from several directions at once. A few
steps further on, we can see what is taking place. The brush has been
cut down and piled up in heaps to the height of a yard or more,
between which the trunks of the large trees stand up like the last
pillars of a magnificent ruined building. These, too, present a
melancholy spectacle: the destructive Makonde have ringed them—
cut a broad strip of bark all round to ensure their dying off—and also
piled up pyramids of brush round them. Father and son, mother and
son-in-law, are chopping away perseveringly in the background—too
busy, almost, to look round at the white stranger, who usually excites
so much interest. If you pass by the same place a week later, the piles
of brushwood have disappeared and a thick layer of ashes has taken
the place of the green forest. The large trees stretch their
smouldering trunks and branches in dumb accusation to heaven—if
they have not already fallen and been more or less reduced to ashes,
perhaps only showing as a white stripe on the dark ground.
This work of destruction is carried out by the Makonde alike on the
virgin forest and on the bush which has sprung up on sites already
cultivated and deserted. In the second case they are saved the trouble
of burning the large trees, these being entirely absent in the
secondary bush.
After burning this piece of forest ground and loosening it with the
hoe, the native sows his corn and plants his vegetables. All over the
country, he goes in for bed-culture, which requires, and, in fact,
receives, the most careful attention. Weeds are nowhere tolerated in
the south of German East Africa. The crops may fail on the plains,
where droughts are frequent, but never on the plateau with its
abundant rains and heavy dews. Its fortunate inhabitants even have
the satisfaction of seeing the proud Wayao and Wamakua working
for them as labourers, driven by hunger to serve where they were
accustomed to rule.
But the light, sandy soil is soon exhausted, and would yield no
harvest the second year if cultivated twice running. This fact has
been familiar to the native for ages; consequently he provides in
time, and, while his crop is growing, prepares the next plot with axe
and firebrand. Next year he plants this with his various crops and
lets the first piece lie fallow. For a short time it remains waste and
desolate; then nature steps in to repair the destruction wrought by
man; a thousand new growths spring out of the exhausted soil, and
even the old stumps put forth fresh shoots. Next year the new growth
is up to one’s knees, and in a few years more it is that terrible,
impenetrable bush, which maintains its position till the black
occupier of the land has made the round of all the available sites and
come back to his starting point.
The Makonde are, body and soul, so to speak, one with this bush.
According to my Yao informants, indeed, their name means nothing
else but “bush people.” Their own tradition says that they have been
settled up here for a very long time, but to my surprise they laid great
stress on an original immigration. Their old homes were in the
south-east, near Mikindani and the mouth of the Rovuma, whence
their peaceful forefathers were driven by the continual raids of the
Sakalavas from Madagascar and the warlike Shirazis[47] of the coast,
to take refuge on the almost inaccessible plateau. I have studied
African ethnology for twenty years, but the fact that changes of
population in this apparently quiet and peaceable corner of the earth
could have been occasioned by outside enterprises taking place on
the high seas, was completely new to me. It is, no doubt, however,
correct.
The charming tribal legend of the Makonde—besides informing us
of other interesting matters—explains why they have to live in the
thickest of the bush and a long way from the edge of the plateau,
instead of making their permanent homes beside the purling brooks
and springs of the low country.
“The place where the tribe originated is Mahuta, on the southern
side of the plateau towards the Rovuma, where of old time there was
nothing but thick bush. Out of this bush came a man who never
washed himself or shaved his head, and who ate and drank but little.
He went out and made a human figure from the wood of a tree
growing in the open country, which he took home to his abode in the
bush and there set it upright. In the night this image came to life and
was a woman. The man and woman went down together to the
Rovuma to wash themselves. Here the woman gave birth to a still-
born child. They left that place and passed over the high land into the
valley of the Mbemkuru, where the woman had another child, which
was also born dead. Then they returned to the high bush country of
Mahuta, where the third child was born, which lived and grew up. In
course of time, the couple had many more children, and called
themselves Wamatanda. These were the ancestral stock of the
Makonde, also called Wamakonde,[48] i.e., aborigines. Their
forefather, the man from the bush, gave his children the command to
bury their dead upright, in memory of the mother of their race who
was cut out of wood and awoke to life when standing upright. He also
warned them against settling in the valleys and near large streams,
for sickness and death dwelt there. They were to make it a rule to
have their huts at least an hour’s walk from the nearest watering-
place; then their children would thrive and escape illness.”
The explanation of the name Makonde given by my informants is
somewhat different from that contained in the above legend, which I
extract from a little book (small, but packed with information), by
Pater Adams, entitled Lindi und sein Hinterland. Otherwise, my
results agree exactly with the statements of the legend. Washing?
Hapana—there is no such thing. Why should they do so? As it is, the
supply of water scarcely suffices for cooking and drinking; other
people do not wash, so why should the Makonde distinguish himself
by such needless eccentricity? As for shaving the head, the short,
woolly crop scarcely needs it,[49] so the second ancestral precept is
likewise easy enough to follow. Beyond this, however, there is
nothing ridiculous in the ancestor’s advice. I have obtained from
various local artists a fairly large number of figures carved in wood,
ranging from fifteen to twenty-three inches in height, and
representing women belonging to the great group of the Mavia,
Makonde, and Matambwe tribes. The carving is remarkably well
done and renders the female type with great accuracy, especially the
keloid ornamentation, to be described later on. As to the object and
meaning of their works the sculptors either could or (more probably)
would tell me nothing, and I was forced to content myself with the
scanty information vouchsafed by one man, who said that the figures
were merely intended to represent the nembo—the artificial
deformations of pelele, ear-discs, and keloids. The legend recorded
by Pater Adams places these figures in a new light. They must surely
be more than mere dolls; and we may even venture to assume that
they are—though the majority of present-day Makonde are probably
unaware of the fact—representations of the tribal ancestress.
 The references in the legend to the descent from Mahuta to the
Rovuma, and to a journey across the highlands into the Mbekuru
valley, undoubtedly indicate the previous history of the tribe, the
travels of the ancestral pair typifying the migrations of their
descendants. The descent to the neighbouring Rovuma valley, with
its extraordinary fertility and great abundance of game, is intelligible
at a glance—but the crossing of the Lukuledi depression, the ascent
to the Rondo Plateau and the descent to the Mbemkuru, also lie
within the bounds of probability, for all these districts have exactly
the same character as the extreme south. Now, however, comes a
point of especial interest for our bacteriological age. The primitive
Makonde did not enjoy their lives in the marshy river-valleys.
Disease raged among them, and many died. It was only after they
had returned to their original home near Mahuta, that the health
conditions of these people improved. We are very apt to think of the
African as a stupid person whose ignorance of nature is only equalled
by his fear of it, and who looks on all mishaps as caused by evil
spirits and malignant natural powers. It is much more correct to
assume in this case that the people very early learnt to distinguish
districts infested with malaria from those where it is absent.
This knowledge is crystallized in the
ancestral warning against settling in the
valleys and near the great waters, the
dwelling-places of disease and death. At the
same time, for security against the hostile
Mavia south of the Rovuma, it was enacted
that every settlement must be not less than a
certain distance from the southern edge of the
plateau. Such in fact is their mode of life at the
present day. It is not such a bad one, and
certainly they are both safer and more
comfortable than the Makua, the recent
intruders from the south, who have made USUAL METHOD OF
good their footing on the western edge of the CLOSING HUT-DOOR
plateau, extending over a fairly wide belt of
country. Neither Makua nor Makonde show in their dwellings
anything of the size and comeliness of the Yao houses in the plain,
especially at Masasi, Chingulungulu and Zuza’s. Jumbe Chauro, a
Makonde hamlet not far from Newala, on the road to Mahuta, is the
most important settlement of the tribe I have yet seen, and has fairly
spacious huts. But how slovenly is their construction compared with
the palatial residences of the elephant-hunters living in the plain.
The roofs are still more untidy than in the general run of huts during
the dry season, the walls show here and there the scanty beginnings
or the lamentable remains of the mud plastering, and the interior is a
veritable dog-kennel; dirt, dust and disorder everywhere. A few huts
only show any attempt at division into rooms, and this consists
merely of very roughly-made bamboo partitions. In one point alone
have I noticed any indication of progress—in the method of fastening
the door. Houses all over the south are secured in a simple but
ingenious manner. The door consists of a set of stout pieces of wood
or bamboo, tied with bark-string to two cross-pieces, and moving in
two grooves round one of the door-posts, so as to open inwards. If
the owner wishes to leave home, he takes two logs as thick as a man’s
upper arm and about a yard long. One of these is placed obliquely
against the middle of the door from the inside, so as to form an angle
of from 60° to 75° with the ground. He then places the second piece
horizontally across the first, pressing it downward with all his might.
It is kept in place by two strong posts planted in the ground a few
inches inside the door. This fastening is absolutely safe, but of course
cannot be applied to both doors at once, otherwise how could the
owner leave or enter his house? I have not yet succeeded in finding
out how the back door is fastened.

MAKONDE LOCK AND KEY AT JUMBE CHAURO

 This is the general way of closing a house. The Makonde at Jumbe
Chauro, however, have a much more complicated, solid and original
one. Here, too, the door is as already described, except that there is
only one post on the inside, standing by itself about six inches from
one side of the doorway. Opposite this post is a hole in the wall just
large enough to admit a man’s arm. The door is closed inside by a
large wooden bolt passing through a hole in this post and pressing
with its free end against the door. The other end has three holes into
which fit three pegs running in vertical grooves inside the post. The
door is opened with a wooden key about a foot long, somewhat
curved and sloped off at the butt; the other end has three pegs
corresponding to the holes, in the bolt, so that, when it is thrust
through the hole in the wall and inserted into the rectangular
opening in the post, the pegs can be lifted and the bolt drawn out.[50]

MODE OF INSERTING THE KEY

With no small pride first one householder and then a second

showed me on the spot the action of this greatest invention of the
Makonde Highlands. To both with an admiring exclamation of
“Vizuri sana!” (“Very fine!”). I expressed the wish to take back these
marvels with me to Ulaya, to show the Wazungu what clever fellows
the Makonde are. Scarcely five minutes after my return to camp at
Newala, the two men came up sweating under the weight of two
heavy logs which they laid down at my feet, handing over at the same
time the keys of the fallen fortress. Arguing, logically enough, that if
the key was wanted, the lock would be wanted with it, they had taken
their axes and chopped down the posts—as it never occurred to them
to dig them out of the ground and so bring them intact. Thus I have
two badly damaged specimens, and the owners, instead of praise,
come in for a blowing-up.
The Makua huts in the environs of Newala are especially
miserable; their more than slovenly construction reminds one of the
temporary erections of the Makua at Hatia’s, though the people here
have not been concerned in a war. It must therefore be due to
congenital idleness, or else to the absence of a powerful chief. Even
the baraza at Mlipa’s, a short hour’s walk south-east of Newala,
shares in this general neglect. While public buildings in this country
are usually looked after more or less carefully, this is in evident
danger of being blown over by the first strong easterly gale. The only
attractive object in this whole district is the grave of the late chief
Mlipa. I visited it in the morning, while the sun was still trying with
partial success to break through the rolling mists, and the circular
grove of tall euphorbias, which, with a broken pot, is all that marks
the old king’s resting-place, impressed one with a touch of pathos.
Even my very materially-minded carriers seemed to feel something
of the sort, for instead of their usual ribald songs, they chanted
solemnly, as we marched on through the dense green of the Makonde
bush:—
 “We shall arrive with the great master; we stand in a row and have
no fear about getting our food and our money from the Serkali (the
Government). We are not afraid; we are going along with the great
master, the lion; we are going down to the coast and back.”
With regard to the characteristic features of the various tribes here
on the western edge of the plateau, I can arrive at no other
conclusion than the one already come to in the plain, viz., that it is
impossible for anyone but a trained anthropologist to assign any
given individual at once to his proper tribe. In fact, I think that even
an anthropological specialist, after the most careful examination,
might find it a difficult task to decide. The whole congeries of peoples
collected in the region bounded on the west by the great Central
African rift, Tanganyika and Nyasa, and on the east by the Indian
Ocean, are closely related to each other—some of their languages are
only distinguished from one another as dialects of the same speech,
and no doubt all the tribes present the same shape of skull and
structure of skeleton. Thus, surely, there can be no very striking
differences in outward appearance.
 Even did such exist, I should have no time
to concern myself with them, for day after day,
I have to see or hear, as the case may be—in
any case to grasp and record—an
extraordinary number of ethnographic
phenomena. I am almost disposed to think it
fortunate that some departments of inquiry, at
least, are barred by external circumstances.
Chief among these is the subject of iron-
working. We are apt to think of Africa as a
country where iron ore is everywhere, so to
speak, to be picked up by the roadside, and
where it would be quite surprising if the
inhabitants had not learnt to smelt the
material ready to their hand. In fact, the
knowledge of this art ranges all over the
continent, from the Kabyles in the north to the
Kafirs in the south. Here between the Rovuma
and the Lukuledi the conditions are not so
favourable. According to the statements of the
Makonde, neither ironstone nor any other
form of iron ore is known to them. They have
not therefore advanced to the art of smelting
the metal, but have hitherto bought all their
THE ANCESTRESS OF
THE MAKONDE
iron implements from neighbouring tribes.
Even in the plain the inhabitants are not much
better off. Only one man now living is said to
understand the art of smelting iron. This old fundi lives close to
Huwe, that isolated, steep-sided block of granite which rises out of
the green solitude between Masasi and Chingulungulu, and whose
jagged and splintered top meets the traveller’s eye everywhere. While
still at Masasi I wished to see this man at work, but was told that,
frightened by the rising, he had retired across the Rovuma, though
he would soon return. All subsequent inquiries as to whether the
fundi had come back met with the genuine African answer, “Bado”
(“Not yet”).
 BRAZIER

Some consolation was afforded me by a brassfounder, whom I

came across in the bush near Akundonde’s. This man is the favourite
of women, and therefore no doubt of the gods; he welds the glittering
brass rods purchased at the coast into those massive, heavy rings
which, on the wrists and ankles of the local fair ones, continually give
me fresh food for admiration. Like every decent master-craftsman he
had all his tools with him, consisting of a pair of bellows, three
crucibles and a hammer—nothing more, apparently. He was quite
willing to show his skill, and in a twinkling had fixed his bellows on
the ground. They are simply two goat-skins, taken off whole, the four
legs being closed by knots, while the upper opening, intended to
admit the air, is kept stretched by two pieces of wood. At the lower
end of the skin a smaller opening is left into which a wooden tube is
stuck. The fundi has quickly borrowed a heap of wood-embers from
the nearest hut; he then fixes the free ends of the two tubes into an
earthen pipe, and clamps them to the ground by means of a bent
piece of wood. Now he fills one of his small clay crucibles, the dross
on which shows that they have been long in use, with the yellow
material, places it in the midst of the embers, which, at present are
only faintly glimmering, and begins his work. In quick alternation
the smith’s two hands move up and down with the open ends of the
bellows; as he raises his hand he holds the slit wide open, so as to let
the air enter the skin bag unhindered. In pressing it down he closes
the bag, and the air puffs through the bamboo tube and clay pipe into
the fire, which quickly burns up. The smith, however, does not keep
on with this work, but beckons to another man, who relieves him at
the bellows, while he takes some more tools out of a large skin pouch
carried on his back. I look on in wonder as, with a smooth round
stick about the thickness of a finger, he bores a few vertical holes into
the clean sand of the soil. This should not be difficult, yet the man
seems to be taking great pains over it. Then he fastens down to the
ground, with a couple of wooden clamps, a neat little trough made by
splitting a joint of bamboo in half, so that the ends are closed by the
two knots. At last the yellow metal has attained the right consistency,
and the fundi lifts the crucible from the fire by means of two sticks
split at the end to serve as tongs. A short swift turn to the left—a
tilting of the crucible—and the molten brass, hissing and giving forth
clouds of smoke, flows first into the bamboo mould and then into the
holes in the ground.
The technique of this backwoods craftsman may not be very far
advanced, but it cannot be denied that he knows how to obtain an
adequate result by the simplest means. The ladies of highest rank in
this country—that is to say, those who can afford it, wear two kinds
of these massive brass rings, one cylindrical, the other semicircular
in section. The latter are cast in the most ingenious way in the
bamboo mould, the former in the circular hole in the sand. It is quite
a simple matter for the fundi to fit these bars to the limbs of his fair
customers; with a few light strokes of his hammer he bends the
pliable brass round arm or ankle without further inconvenience to
the wearer.
SHAPING THE POT

SMOOTHING WITH MAIZE-COB

CUTTING THE EDGE

 FINISHING THE BOTTOM

LAST SMOOTHING BEFORE

BURNING

FIRING THE BRUSH-PILE

 LIGHTING THE FARTHER SIDE OF
THE PILE

TURNING THE RED-HOT VESSEL

NYASA WOMAN MAKING POTS AT MASASI

Pottery is an art which must always and everywhere excite the
interest of the student, just because it is so intimately connected with
the development of human culture, and because its relics are one of
the principal factors in the reconstruction of our own condition in
prehistoric times. I shall always remember with pleasure the two or
three afternoons at Masasi when Salim Matola’s mother, a slightly-
built, graceful, pleasant-looking woman, explained to me with
touching patience, by means of concrete illustrations, the ceramic art
of her people. The only implements for this primitive process were a
lump of clay in her left hand, and in the right a calabash containing
the following valuables: the fragment of a maize-cob stripped of all
its grains, a smooth, oval pebble, about the size of a pigeon’s egg, a
few chips of gourd-shell, a bamboo splinter about the length of one’s
hand, a small shell, and a bunch of some herb resembling spinach.
 Nothing more. The woman scraped with the
shell a round, shallow hole in the soft, fine
sand of the soil, and, when an active young
girl had filled the calabash with water for her,
she began to knead the clay. As if by magic it
gradually assumed the shape of a rough but
already well-shaped vessel, which only wanted
a little touching up with the instruments
before mentioned. I looked out with the
MAKUA WOMAN closest attention for any indication of the use
MAKING A POT. of the potter’s wheel, in however rudimentary
SHOWS THE a form, but no—hapana (there is none). The
BEGINNINGS OF THE embryo pot stood firmly in its little
POTTER’S WHEEL
depression, and the woman walked round it in
a stooping posture, whether she was removing
small stones or similar foreign bodies with the maize-cob, smoothing
the inner or outer surface with the splinter of bamboo, or later, after
letting it dry for a day, pricking in the ornamentation with a pointed
bit of gourd-shell, or working out the bottom, or cutting the edge
with a sharp bamboo knife, or giving the last touches to the finished
vessel. This occupation of the women is infinitely toilsome, but it is
without doubt an accurate reproduction of the process in use among
our ancestors of the Neolithic and Bronze ages.
There is no doubt that the invention of pottery, an item in human
progress whose importance cannot be over-estimated, is due to
women. Rough, coarse and unfeeling, the men of the horde range
over the countryside. When the united cunning of the hunters has
succeeded in killing the game; not one of them thinks of carrying
home the spoil. A bright fire, kindled by a vigorous wielding of the
drill, is crackling beside them; the animal has been cleaned and cut
up secundum artem, and, after a slight singeing, will soon disappear
under their sharp teeth; no one all this time giving a single thought
to wife or child.
To what shifts, on the other hand, the primitive wife, and still more
the primitive mother, was put! Not even prehistoric stomachs could
endure an unvarying diet of raw food. Something or other suggested
the beneficial effect of hot water on the majority of approved but
indigestible dishes. Perhaps a neighbour had tried holding the hard
roots or tubers over the fire in a calabash filled with water—or maybe
an ostrich-egg-shell, or a hastily improvised vessel of bark. They
became much softer and more palatable than they had previously
been; but, unfortunately, the vessel could not stand the fire and got
charred on the outside. That can be remedied, thought our
ancestress, and plastered a layer of wet clay round a similar vessel.
This is an improvement; the cooking utensil remains uninjured, but
the heat of the fire has shrunk it, so that it is loose in its shell. The
next step is to detach it, so, with a firm grip and a jerk, shell and
kernel are separated, and pottery is invented. Perhaps, however, the
discovery which led to an intelligent use of the burnt-clay shell, was
made in a slightly different way. Ostrich-eggs and calabashes are not
to be found in every part of the world, but everywhere mankind has
arrived at the art of making baskets out of pliant materials, such as
bark, bast, strips of palm-leaf, supple twigs, etc. Our inventor has no
water-tight vessel provided by nature. “Never mind, let us line the
basket with clay.” This answers the purpose, but alas! the basket gets
burnt over the blazing fire, the woman watches the process of
cooking with increasing uneasiness, fearing a leak, but no leak
appears. The food, done to a turn, is eaten with peculiar relish; and
the cooking-vessel is examined, half in curiosity, half in satisfaction
at the result. The plastic clay is now hard as stone, and at the same
time looks exceedingly well, for the neat plaiting of the burnt basket
is traced all over it in a pretty pattern. Thus, simultaneously with
pottery, its ornamentation was invented.
Primitive woman has another claim to respect. It was the man,
roving abroad, who invented the art of producing fire at will, but the
woman, unable to imitate him in this, has been a Vestal from the
earliest times. Nothing gives so much trouble as the keeping alight of
the smouldering brand, and, above all, when all the men are absent
from the camp. Heavy rain-clouds gather, already the first large
drops are falling, the first gusts of the storm rage over the plain. The
little flame, a greater anxiety to the woman than her own children,
flickers unsteadily in the blast. What is to be done? A sudden thought
occurs to her, and in an instant she has constructed a primitive hut
out of strips of bark, to protect the flame against rain and wind.
This, or something very like it, was the way in which the principle
of the house was discovered; and even the most hardened misogynist
cannot fairly refuse a woman the credit of it. The protection of the
hearth-fire from the weather is the germ from which the human
dwelling was evolved. Men had little, if any share, in this forward
step, and that only at a late stage. Even at the present day, the
plastering of the housewall with clay and the manufacture of pottery
are exclusively the women’s business. These are two very significant
survivals. Our European kitchen-garden, too, is originally a woman’s
invention, and the hoe, the primitive instrument of agriculture, is,
characteristically enough, still used in this department. But the
noblest achievement which we owe to the other sex is unquestionably
the art of cookery. Roasting alone—the oldest process—is one for
which men took the hint (a very obvious one) from nature. It must
have been suggested by the scorched carcase of some animal
overtaken by the destructive forest-fires. But boiling—the process of
improving organic substances by the help of water heated to boiling-
point—is a much later discovery. It is so recent that it has not even
yet penetrated to all parts of the world. The Polynesians understand
how to steam food, that is, to cook it, neatly wrapped in leaves, in a
hole in the earth between hot stones, the air being excluded, and
(sometimes) a few drops of water sprinkled on the stones; but they
do not understand boiling.
To come back from this digression, we find that the slender Nyasa
woman has, after once more carefully examining the finished pot,
put it aside in the shade to dry. On the following day she sends me
word by her son, Salim Matola, who is always on hand, that she is
going to do the burning, and, on coming out of my house, I find her
already hard at work. She has spread on the ground a layer of very
dry sticks, about as thick as one’s thumb, has laid the pot (now of a
yellowish-grey colour) on them, and is piling brushwood round it.
My faithful Pesa mbili, the mnyampara, who has been standing by,
most obligingly, with a lighted stick, now hands it to her. Both of
them, blowing steadily, light the pile on the lee side, and, when the
flame begins to catch, on the weather side also. Soon the whole is in a
blaze, but the dry fuel is quickly consumed and the fire dies down, so
that we see the red-hot vessel rising from the ashes. The woman
turns it continually with a long stick, sometimes one way and
sometimes another, so that it may be evenly heated all over. In
twenty minutes she rolls it out of the ash-heap, takes up the bundle
of spinach, which has been lying for two days in a jar of water, and
sprinkles the red-hot clay with it. The places where the drops fall are
marked by black spots on the uniform reddish-brown surface. With a
sigh of relief, and with visible satisfaction, the woman rises to an
erect position; she is standing just in a line between me and the fire,
from which a cloud of smoke is just rising: I press the ball of my
camera, the shutter clicks—the apotheosis is achieved! Like a
priestess, representative of her inventive sex, the graceful woman
stands: at her feet the hearth-fire she has given us beside her the
invention she has devised for us, in the background the home she has
built for us.
At Newala, also, I have had the manufacture of pottery carried on
in my presence. Technically the process is better than that already
described, for here we find the beginnings of the potter’s wheel,
which does not seem to exist in the plains; at least I have seen
nothing of the sort. The artist, a frightfully stupid Makua woman, did
not make a depression in the ground to receive the pot she was about
to shape, but used instead a large potsherd. Otherwise, she went to
work in much the same way as Salim’s mother, except that she saved
herself the trouble of walking round and round her work by squatting
at her ease and letting the pot and potsherd rotate round her; this is
surely the first step towards a machine. But it does not follow that
the pot was improved by the process. It is true that it was beautifully
rounded and presented a very creditable appearance when finished,
but the numerous large and small vessels which I have seen, and, in
part, collected, in the “less advanced” districts, are no less so. We
moderns imagine that instruments of precision are necessary to
produce excellent results. Go to the prehistoric collections of our
museums and look at the pots, urns and bowls of our ancestors in the
dim ages of the past, and you will at once perceive your error.
MAKING LONGITUDINAL CUT IN
BARK

DRAWING THE BARK OFF THE LOG

REMOVING THE OUTER BARK

 BEATING THE BARK

WORKING THE BARK-CLOTH AFTER BEATING, TO MAKE IT

SOFT

MANUFACTURE OF BARK-CLOTH AT NEWALA

To-day, nearly the whole population of German East Africa is
clothed in imported calico. This was not always the case; even now in
some parts of the north dressed skins are still the prevailing wear,
and in the north-western districts—east and north of Lake
Tanganyika—lies a zone where bark-cloth has not yet been
superseded. Probably not many generations have passed since such
bark fabrics and kilts of skins were the only clothing even in the
south. Even to-day, large quantities of this bright-red or drab
material are still to be found; but if we wish to see it, we must look in
the granaries and on the drying stages inside the native huts, where
it serves less ambitious uses as wrappings for those seeds and fruits
which require to be packed with special care. The salt produced at
Masasi, too, is packed for transport to a distance in large sheets of
bark-cloth. Wherever I found it in any degree possible, I studied the
process of making this cloth. The native requisitioned for the
purpose arrived, carrying a log between two and three yards long and
as thick as his thigh, and nothing else except a curiously-shaped
mallet and the usual long, sharp and pointed knife which all men and
boys wear in a belt at their backs without a sheath—horribile dictu!
[51]
Silently he squats down before me, and with two rapid cuts has
drawn a couple of circles round the log some two yards apart, and
slits the bark lengthwise between them with the point of his knife.
With evident care, he then scrapes off the outer rind all round the
log, so that in a quarter of an hour the inner red layer of the bark
shows up brightly-coloured between the two untouched ends. With
some trouble and much caution, he now loosens the bark at one end,
and opens the cylinder. He then stands up, takes hold of the free
edge with both hands, and turning it inside out, slowly but steadily
pulls it off in one piece. Now comes the troublesome work of
scraping all superfluous particles of outer bark from the outside of
the long, narrow piece of material, while the inner side is carefully
scrutinised for defective spots. At last it is ready for beating. Having
signalled to a friend, who immediately places a bowl of water beside
him, the artificer damps his sheet of bark all over, seizes his mallet,
lays one end of the stuff on the smoothest spot of the log, and
hammers away slowly but continuously. “Very simple!” I think to
myself. “Why, I could do that, too!”—but I am forced to change my
opinions a little later on; for the beating is quite an art, if the fabric is
not to be beaten to pieces. To prevent the breaking of the fibres, the
stuff is several times folded across, so as to interpose several
thicknesses between the mallet and the block. At last the required
state is reached, and the fundi seizes the sheet, still folded, by both
ends, and wrings it out, or calls an assistant to take one end while he
holds the other. The cloth produced in this way is not nearly so fine
and uniform in texture as the famous Uganda bark-cloth, but it is
quite soft, and, above all, cheap.
Now, too, I examine the mallet. My craftsman has been using the
simpler but better form of this implement, a conical block of some
hard wood, its base—the striking surface—being scored across and
across with more or less deeply-cut grooves, and the handle stuck
into a hole in the middle. The other and earlier form of mallet is
shaped in the same way, but the head is fastened by an ingenious
network of bark strips into the split bamboo serving as a handle. The
observation so often made, that ancient customs persist longest in
connection with religious ceremonies and in the life of children, here
finds confirmation. As we shall soon see, bark-cloth is still worn
during the unyago,[52] having been prepared with special solemn
ceremonies; and many a mother, if she has no other garment handy,
will still put her little one into a kilt of bark-cloth, which, after all,
looks better, besides being more in keeping with its African
surroundings, than the ridiculous bit of print from Ulaya.
MAKUA WOMEN