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Organic Chemistry
6th Edition
Chapter 31
Paula Yurkanis Bruice
The Organic Chemistry
of Drugs
Discovery
and
Design
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• A drug is any absorbed substance that changes or
enhances a physical or psychological function in the
body.
• A proprietary name (trade name or brand name)
identifies a commercial product and distinguishes it
from other products.
• Each drug is also given a generic name that any
pharmaceutical company can use to identify the
product.
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Some Examples of Drugs
Proprietary
name
Trimox®
Generic
name
amoxicillin
antibiotic
®
Premarin conjugated
estrogens
hormone replacement
therapy
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• The goal of the medicinal chemist is to find
compounds that have potent effects on given
diseases, with minimal side effects.
• A naturally occurring drug can serve as a prototype
(lead compound).
• Analogs of the lead compounds are synthesized
to improve the therapeutic properties or side
effects.
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Molecular Modification Improves the Therapeutic
Properties of Cocaine
Local anesthetic, but also
affects central nervous
system
Retains the local
anesthetic property
without CNS effects
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Anesthetics Obtained by Molecular Modification
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Replacing the ester linkage of procaine with an amide
linkage led to procainamide hydrochloride:
• Active as a cardiac depressant
• Active as a local anesthetic
• Used clinically as an antiarrhythmic
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Molecular Modification of Morphine
Morphine and all the compounds prepared by molecular
modification of morphine have a structural feature in
common
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Molecular Modification of Codeine
Dextromethorphan is the major ingredient in most cough
medicines
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Random Screening
In the development of most drugs, the lead compound
is found by screening thousands of compounds randomly
A random screen, or a blind screen, is a search for a
pharmacologically active lead compound without any
information about what structures might show activity
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Serendipity in Drug Development
The tranquilizer Librium was discovered accidentally
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Structural modification of Librium led to the generation
of other tranquilizers:
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• Many drugs exert their physiological effects by binding
to a specific cellular binding site, called a receptor.
• A drug interacts with its receptor by hydrogen
bonding, electrostatic attractions, and hydrophobic
(van der Waals) interactions.
• The most important factor in the interaction between a
drug and a receptor is a snug fit.
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Excess histamine in the body causes the symptoms
associated with the common cold and allergic responses:
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Antihistamines alleviate the action of histamine by
binding to the histamine receptor:
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Acetylcholine is a neurotransmitter that enhances
peristalsis, wakefulness, and memory:
The binding sites of cholinergic receptors are structurally
similar to the binding sites of histamine receptors
The antihistamine diphenhydramine has been used to
treat insomnia and motion sickness
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4-Methylhistamine was used as a lead compound to
develop antiulcer drugs:
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When modified compounds are screened, it is possible
to find a compound whose pharmacological activity
is completely different from that of the lead compound:
an antibiotic
a drug with
hypoglycemic activity
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Molecular modification of promethazine led to the
discovery of the tricyclic antipsychotic drugs:
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Drugs as Enzyme Inhibitors
Penicillin destroys bacteria by inhibiting the enzyme that
synthesizes bacterial cell walls:
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Bacteria develop resistance to penicillin by secreting
penicillinase, which destroys penicillin:
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Chemists have developed drugs that inhibit penicillinase:
Administering penicillin and the sulfone in combination
results in drug synergism
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Mechanism of Penicillinase Inhibition by Sulfone
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The following two antimicrobial agents are given in
combination to treat tuberculosis:
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•
The therapeutic index is the ratio of the lethal dose
to the therapeutic dose.
• The higher the therapeutic index, the greater is the
drug’s margin of safety.
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A Suicide Substrate That Inactivates
Transamination
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Approach in Rational Drug Design
• To correlate the known physical or chemical property
of a series of compounds with biological activity
• To correlate the property of a drug with a specific
activity
• To use the existing knowledge to design compounds
that possess the desirable activity
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The biological activity of a drug depends on two
properties:
• Distribution
• Binding
Distribution coefficient: the ratio of the amount dissolving
in 1-octanol to the amount dissolving in water
Compounds with a lower distribution coefficient cannot
penetrate the cell membrane
Compounds with a higher distribution coefficient cannot
cross the aqueous phase
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The technique of relating a property of a series of
compounds to biological activity is known as a
quantitative structure–activity relationship (QSAR):
potency = 0.8p – 7.34s – 8.14
•
The s parameter measures the electron-donating or electronwithdrawing properties of R and R.
•
The p parameter measures the hydrophobicity of R and R.
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The potency of an analgesic was found to be described
by the following equation:
HA indicates whether R is a hydrogen bond acceptor and
where B is a steric factor
Analysis indicated that the vinyl-substituted compound
should be prepared
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Utilization of Computer
Molecular Modeling to
Facilitate Rational Drug
Design
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Search for New Drugs by Mass Production
Combinatorial Organic Synthesis
This approach has been used to create a library of
benzodiazepines:
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Antiviral Drugs
These nucleoside analogs interfere with DNA or
RNA synthesis
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