The seminar presented by Noor Saba discusses structure modification in medicinal chemistry to enhance drug potency and therapeutic index. It covers various examples, such as the modification of hormones and neuroleptic drugs, and explains the concept of therapeutic index as a measure of drug safety. The document emphasizes the need for modifications to improve pharmacokinetic and pharmacodynamic properties, noting that a lower therapeutic index may be acceptable for treatments of severe diseases like cancer or AIDS.

1. Seminar presented on,
STRUCTURE MODIFICATION TO INCREASE POTENCY AND
THERAPEUTIC INDEX
2022-2023
Presented by
NOOR SABA. D. G
Register No.: P11AZ22S104021
I M.Sc., I Semester.

2. Contents:
• Introduction
• Definition
• Structure with examples
• Therapeutic index
• Advantages
• Reference
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3. Introduction:
1. It is a tool of research in medicinal chemistry to refine molecule.
2.Most of the molecules are modified either by altering its physical
properties or by modifying chemical structure.
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4. Structure modification:
• Structure modification is chemical alteration of known and previously characterized.
• lead compound for the purpose of enhancing its usefulness as a drug (to improve activity).
• This could mean enhancing its specificity for a particular body target site, increasing its
potency.
Examples:
1. Progesterone and estradiol among the sex hormones
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5. 1.Sulpur atom of the phenothiazine a neuroleptic drug is replaced by alkane or alkene
bioisosteres then dibenzepine a antidepressant drug will be formed.
Phenothiazine
Dibenzazepine
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Examples:

6. 2. Naturally occuring harmone estradiol and the synthetic unalogue diethylstibestrol.
• The Trans isomer of diethylstilbestrol has approximately the same potency as estradiol
where as cis isomer is only 1/14 as a active .
• In the trans configuration ,the phenolic hydroxyl group mimic the correct orientation of
the phenol and alcohol in estradiol this is not possible with the cis isomer and more
flexible analogue have little or no activity.
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7. Therapeutic index:
It is a quantitative measurement of relatively safety of a drug.
The ratio of the concentration of a drug that give undesirable effect to that which
give desirable effect.
TI(humans)=TD50/ED50
TI(animals)=LD50/ED50
Lethal dose (LD50):This is the dose which would kill one half of limited population
of the same species and strain.
Effective dose (ED50):This is the dose which produces desired response in 50% of
test population.
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9. • The larger the therapeutic index, the greater margin of safety of the
compound.
• One source of toxicity (hepato toxicity, cardio toxicity)derives from
particular substructure of molecule known as toxicophore or structural
alerts.
Types:
1. Wide TI.
2. Narrow TI.
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10. Chlorambucil
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There is no specific minimum value for a therapeutic index that must be attained
before a drug can be approved it depends on the disease that is being treated and
whether there are already other therapies available a low therapeutic index is tolerable
for lethal dis-cases such as cancer or AIDS especially if there is no other treatment
available or if the side effect is minor compared with the treatment benefit for less
threatening disease therapeutic indices on the order of 10-100 may be reasonable
agent chlorambucil is 23 and for ethanol it is 10.

11. Advantages:
• They improve pharmacokinetic properties .
• They improve pharmacodynamic properties.
• They are more affordable.
• They can create new pharmacological properties.
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12. Reference:
• https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-
science/molecular-modification.
• The organic chemistry of drug design and drug action. (page number -59 to 61)
- Mark W. Holladay , Richard B. Silverman.
• Modification in drug design clinical chemistry.
- John gajecoski.
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13. Thank you