MOLECULAR MODIFICATIONS

BY
Dr.K.G.LALITHA
PROFESSOR
DEPT OF PHARMACEUTICAL CHEMISTRY
JAZAN UNIVERSITY,KSA

Subject: Drug Discovery and Development

Lecture notes – 3rd year, 6th semester, Pharm.D

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• Molecular modifications on the lead is an important
drug design strategy for optimization of the lead

• SAR studies is an important traditional method to

optimize the lead. Molecular modification is one of
the SAR studies carried out on the lead.

• Molecular modifications on the lead may involve

modification of a region like a ring structure or
modification of a functional group or substituent to
improve the pharmacodynamic and
pharmacokinetic properties of the lead
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 METHODS OF MOLECULAR MODIFICATIONS

I.Introduction of new substituents:

May increase or decrease activity by influencing the

binding to target
May influence pharmacokinetics of the drug
Examples already discussed in lead optimization

II. Variation of substituents:

1.Repalcement of alkyl substituents:

 Varying alkyl substituents would affect the binding

interactions of the drug with target, may also influence
absorption and metabolism 3
 The alkyl substituents of ethers, esters, amides, amines
can be easily removed or replaced by another substituent
 The alkyl substituent which are part of the carbon skeleton
of the molecule are not easily removed, they need
complete synthesis
Eg: drug N CH3 VOC-Cl R’I
drug NH drug NR’
R R
R
amine

2. Introduction of bulky groups:

 If the alkyl groups are interacting with the hydrophobic

pocket in the binding site then increasing the length of the
chain or the bulk of the alkyl group would fill the pocket and
increase the binding interaction 4
 Larger alkyl groups may increase selectivity and
reduce side effects

 Isoprenaline, is an analogue of Adrenaline,

where a methyl group is replaced by a isopropyl
group resulting in selectivity for adrenergic β
receptor over α receptor

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3. Aromatic substituents:

 The position (o,m,or p) and nature of the substituent

(EWG or EDG) on the aromatic ring would influence the
binding interactions

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Varying the position of aromatic substituent
III. Extension of structure or Molecular addition:

 This involves addition of another functional group

to the lead compound to find extra binding
interactions with the target
 This is used to find out extra hydrophobic regions
in a binding site by adding alkyl or aralkyl
functional groups to alcohols, phenols, amines
and carboxylic acids
 May also be used to find out extra hydrogen
bonding or ionic interactions by introducing
additional polar functional groups like –OH,
-NH2. 7
 Example is design of Angiotensin Converting Enzyme
inhibitors

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 The molecule II with phenethyl group has 1000
fold improved inhibition demonstrating that the
extra aromatic ring is binding to a hydrophobic
pocket in the enzyme’s binding site

Cyclizine Meclizine 9
 Meclizine is an antihistamine with less
anticholinergic activity

 Cyclizine has comparatively high

anticholinergic activity

 The additional tolyl group in Meclizine

reduces the interaction of the drug with
cholinergic receptors and make it more
selective to histamine receptors, thereby
reducing the side effects.
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IV. Ring variations:
 Aromatic or heteroaromatic rings in the lead may
be replaced by a range of other heteroaromatic
rings of different ring size and hetero atom
positions.

 This would significantly improve the activity,

selectivity and reduce side effects

 Ring variations may also affect absorption

example: Ticonazole and Fluconazole

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V. Simplification of the structure:
 Simplification is applied on complex lead molecules
obtained from natural sources

 It is important to identify the essential functional groups

for biological activity before carrying out simplification

 The pharmacophore is retained for biological activity and

the non-essential parts of the chemical structure are
removed or modified

 Example is design of synthetic local anesthetics from the

structure of natural alkaloid Cocaine

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C6H5COO- and the tertiary amino group are the essential groups
for local anaesthetic activity of cocaine. They are retained and
the structure is simplified to give Procaine a compound which is
more active than Cocaine and very simple in structure and easy
to synthesize.

The advantage of simpler molecules is that they are easier,

quicker and cheaper to synthesize

The disadvantage is that they are flexible and may result in

reduced activity, reduced selectivity and increased side effects
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Hence over simplification should be avoided
VI. Rigidification of the structure:
 It is used to increase the activity of the drug or to
reduce the side effects.

 Flexible molecules can adopt varieties of

conformations and each conformation may react
with different receptors to elicit various responses
which might be toxic

 Rigidification is to lock the molecule into a more

rigid conformation so that it cannot take up other
shapes or conformations
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 So the interaction with other receptors and side
effects are eliminated

 By blocking the drug into active conformation the

drug is ready to fit to its target receptor and it would
increase the activity

 A rigid molecule which is already in its active

conformation will have better binding affinity

 Incorporating the flexible drug into a ring is the

usual way of locking a conformation
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Morphine Etorphine 16
 Etorphine is 10,000 times more potent than Morphine

 It is because that it is a hydrophobic molecule and can cross

the blood brain barrier 300 times more easily than Morphine
and has 20 times more affinity to the analgesic receptors
because of better binding interactions

 An extra ring inside ring C increases the rigidity of the

structure and therefore increases the binding affinity

 Molecular addition – addition of a lipophilic group, pentyl-2-

alcohol to the 5th position on the phenanthrene ring
increases the activity by providing extra hydrophobic binding
interactions
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 REFERENCE

Graham L.Patrick, An Introduction to

Medicinal Chemistry, Fourth Edition,
Oxford University Press, New York, 2009,
225 - 241

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