Application of Classical Bioisosteres in Drug Design

a. Replacement of Fluorine atoms for Hydrogen

Fluorine is most commonly employed as monovalent bioisosteric replacement for hydrogen. Stearic parameter for hydrogen and fluorine are similar, their Vander waal’s radii being 1.2 and

1.35 A º

respectively. The anti-neoplastic agent 5 fluorouracil is a classical example, in which the fluorine replaced with hydrogen in

5 th

position of Uracil a normal substrate, result in a derivative, which can alter, selected enzymatic derivative. Fluorine in fluorouracil forms a covalent binding with the enzyme and inhibits it.

b. Replacement of $-NH 2$ group by $-CH 3$

An example of this type is oral hypoglycaemic Carbutamide, the $-NH 2$ group is replaced by $-CH 3$ gives Tolbutamide, which possess extended biological half-lives and reduces toxicity.

c. Replacement of – $OH$ by $-SH, NH 2$

Example of this replacement is guanine and 6-thioguanine. The antineoplastic agent 6-thioguanine inhibits the enzyme hypoxanthine-guanine phosphoribosyl transferase and blocks the synthesis of DNA.

Another example is Calcium channel blockers dihydropyrimidines. Substitution of the hydroxyl with thiol group resulted in enhanced potency.

d. Replacement of – $O$ – group by $NH$ group

The replacement of – $O$ – group by $NH$ group in Procaine gives Procainamide. The local anaesthetic activity of Procaine is more than Procainamide due to difference in lipid solubility.

e. Replacement of – CH – for – n

=

The trivalent substitution of – $CH$ – with – $N=$ is commonly used in modern drug design. Substitution of the pyridinyl amino $-N=$ in Mepyramine by $-CH-$ produces Chlorpheniramine withless sedative effect an undesirable side effect of antihistaminic.