Bioisosterism - Introduction

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1. BIOISOSTERISM Submitted by R. ANBARASAN 2 ND M.Sc BIOTECHNOLOGY ANNAMALAI UNIVERSITY

2. CONTENT Introduction Isometric replacement Utilization Classification Changes occur Reference

3. INTRODUCTION ISOSTERISM Langmuir in 1919- compounds or group of atoms with same number of atoms and electrons Eg. , Co 2 , - O=C=O N 2 O –N=N + =O

4. BIOISOSTERES- Burger defines, “substitute or groups with chemical or physical similarities Produce similar biological properties Replacement or modification of functional group with other having similar properties called bioisosteric replacement

5. Why isosteric replacement? Greater selectivity Less side effects Deceased toxicity Improved pharmacokinetics Increase stability

6. UTILITY OF BIOISOSTERES Improving potency Enhancing selectivity Altering physical properties Reducing or redirecting metabolism Eliminating or modifying toxicophores Acquiring novel intellectual property

7. CLASSIFICATION Classified into two types: Classical bioisosteres Non classical bioisosteres

8. Classical bioisosteres are further classified: Univalent atoms and groups (C, N, O, S, -Cl, -Br) Bivalent atoms and groups (R-O-R, R-S-R, R-NH-R) Trivalent atoms and groups (-CH=, -N=, R-N=R) Tetravalent atoms and groups (=C=, =N=, =P=) Ring equivalent

9. Non – classical bioisosteres don’t have same number of atoms It don’t fit for steric and electronic rules But produce similar biological activity Halogens (Cl, F, Br) Ethers (-R-O-R, -S-) Hydroxy groups (-OH) Carboxylic acid group (-R-COOH, R-SOOH) Catechol

10. CHANGES OCCUR: Some changes resulting from bioisosteric replacement Structural (size, shape, H-bonding) Receptor interactions (lipid or water solubility) Pharmacokinetics (lipophilicity, hydrophilicity, Pka , H-bonding)

11. For example; Cyclopropyl group used as bioisosteric for an alkaline group in prodrugs and opioid antagonists Replacing a functional group, important for target binding, but problematic on one way or other For example, thiourea group was present as important binding group in early histamine antagonist but was responsible for toxic side effects replacing it with bioisosteric allow binding without toxicity

12. REFERENCE Prof. S.V. Amrutkar slideshare in SCRIBD www.tubakhanslideshare//slideshare.com Graham L.Patrick book An introduction to medical chemistry