Organic Chemistry

1
Chapter 31 The Organic Chemistry of
Drugs Discovery and Design
Organic Chemistry 6th Edition Paula Yurkanis
Bruice
2

• 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.

3
Some Examples of Drugs
Generic name
Proprietary name

Trimox amoxicillin
antibiotic

Premarin conjugated estrogens
hormone replacement therapy
4
(No Transcript)
5

• 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.

6
Molecular Modification Improves the Therapeutic
Properties of Cocaine
Local anesthetic, but also affects central
nervous system
Retains the local anesthetic property without CNS
effects
7
Anesthetics Obtained by Molecular Modification
8
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

9
Molecular Modification of Morphine
Morphine and all the compounds prepared by
molecular modification of morphine have a
structural feature in common
10
Molecular Modification of Codeine
Dextromethorphan is the major ingredient in most
cough medicines
11
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
12
Serendipity in Drug Development
The tranquilizer Librium was discovered
accidentally
13
Structural modification of Librium led to the
generation of other tranquilizers
14

• 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.

15
Excess histamine in the body causes the
symptoms associated with the common cold and
allergic responses
16
Antihistamines alleviate the action of histamine
by binding to the histamine receptor
17
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
18
4-Methylhistamine was used as a lead compound to
develop antiulcer drugs
19
When modified compounds are screened, it is
possible to find a compound whose
pharmacological activity is completely different
from that of the lead compound
20
Molecular modification of promethazine led to
the discovery of the tricyclic antipsychotic
drugs
21
Drugs as Enzyme Inhibitors
Penicillin destroys bacteria by inhibiting the
enzyme that synthesizes bacterial cell walls
22
Bacteria develop resistance to penicillin by
secreting penicillinase, which destroys
penicillin
23
Chemists have developed drugs that inhibit
penicillinase
Administering penicillin and the sulfone in
combination results in drug synergism
24
Mechanism of Penicillinase Inhibition by Sulfone
25
The following two antimicrobial agents are given
in combination to treat tuberculosis
26

• The therapeutic index is the ratio of the lethal
  dose
• to the therapeutic dose.

• The higher the therapeutic index, the greater is
  the drugs margin of safety.

27
A Suicide Substrate That Inactivates
Transamination
28
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

29
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
30
The technique of relating a property of a series
of compounds to biological activity is known as
a quantitative structureactivity relationship
(QSAR)
potency 0.8p 7.34s 8.14

• The?s parameter measures the electron-donating or
  electron-withdrawing properties of R and R?.

• The?p parameter measures the hydrophobicity of R
  and R?.

31
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
32
Utilization of Computer Molecular Modeling to
Facilitate Rational Drug Design
33
Search for New Drugs by Mass Production Combinator
ial Organic Synthesis
This approach has been used to create a library
of benzodiazepines
34
(No Transcript)
35
Antiviral Drugs
These nucleoside analogs interfere with DNA or
RNA synthesis