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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
name
Trimox®
Generic
name
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
bad effect on the
central nervous system
retains the local
anesthetic property
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
an antibiotic
a drug with
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