Organic Chemistry

4th Edition Chapter 30

Paula Yurkanis Bruice

The Organic Chemistry

of Drugs

Discovery
and
Design

Irene Lee
Case Western Reserve University
Cleveland, OH
©2004, Prentice Hall
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
 Some Examples of Drugs
Proprietary Generic
name name

Trimox® amoxicillin

antibiotic

®
Premarin conjugated
estrogens

hormone replacement
therapy
The goal of the medicinal chemist is to find compounds
that have potent effects on given diseases, with minimum
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
 Molecular Modification to Improve the
Therapeutic Properties of Cocaine

local anesthetic, but retains the local

bad effect on the anesthetic property
central nervous system
Anesthetics Obtained through Molecular
Modification
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

 Molecular Modification of Morphine

Morphine and all the compounds prepared by molecular

modification of morphine have a structural feature in
common
 Molecular Modification of Codeine

Dextromethorphan is the major ingredient in most cough

medicines
 Random Screening

The lead compound for the development of most drugs

is found by screening thousands of compounds randomly

A random screen is a search for a pharmacologically

active lead compound without any information about
what structures might show activity
The tranquilizer Librium was discovered accidentally
Structural modification of Librium leads to the generation
of other tranquilizers
Many drugs exert their physiological effects by binding
to a specific cellular binding site called a receptor

Excess histamine in the body causes the symptoms

associated with the common cold and allergic responses
Antihistamines alleviate the action of histamine by
binding to the histamine receptor
Acetylcholine is a neurohormone that enhances
peristalsis, wakefulness, and memory

Cholinergic receptors are structurally similar to the

histamine receptors

The antihistamine diphenhydramine has been used to

treat insomnia and motion sickness
4-Methylhistamine is used as a lead compound to
develop antiulcer drugs
In screening modified compounds, it is possible to find a
compound with completely different pharmacological
activity than the lead compound

a drug with
an antibiotic
hypoglycemic activity
Molecular modification of promethazine leads to the
discovery of an antipsychotic drug
 Drugs as Enzyme Inhibitors

Penicillin destroys bacteria by inhibiting the enzyme that

synthesizes bacterial cell walls
Bacteria develop resistance to penicillin by secreting
penicillinase which destroys pencillin

penicillinase penicillinase penicillinase

Chemists have developed drugs that inhibit penicillinase

Administering penicillin and the sulfone in combination

results in drug synergism
Mechanism of Penicillinase Inhibition by Sulfone
The following two antimicrobial agents are given in
combination to treat tuberculosis
• The therapeutic index is the ratio of the lethal dose to
the therapeutic dose

• The higher the therapeutic index, the greater is the

margin of safety of the drug
A Suicide Substrate that Inactivates
Transamination
 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
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
The technique of relating a property of a series of
compounds to biological activity is known as a
quantitative structure–activity relationship (QSAR)
NH2

R
N

H2N N R'

a 2,4-diaminopyrimidine
potency = 0.8p – 7.34s – 8.14

s measures the electron-donating or electron-withdrawing

properties of R and R’

p measures the hydrophobicity of R and R’

In a search for a new analgesic,

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
Utilization of Computer Molecular Modeling in
Drug Design
 Search for New Drugs by Mass Production
Combinatorial Organic Synthesis
This approach has been used to create a library of
benzodiazepines
 Antiviral Drugs

These nucleoside analogs interfere with DNA or RNA

synthesis