MOLECULAR MODELING STUDY ON DAPSONE AND SULFONAMIDES COMPARING STRUCTURES AND PROPERTIES WITH RESPECT TO ANTILEPROSY ACTIVITY

Despite the very close structural relationship between dapsone (4,4'-d iaminodiphenyl sulfone, 4,4' sulphonyldianiline, diaphenyl sulphone, D DS) and sulfanilamide (p-aminobenzene sulfonamide), being the prototyp e of all other sulfonamides, only dapsone shows remarkable efficient p harmacological activity against Mycobacterium leprae. Cells of certain micro-organism need para-aminobenzoic acid (PABA), the latter playing the role of natural substrate to biosynthesis of folic acid. Sufones and sulfonamides show competitive antagonism as chemical analogs of PA BA. It is most surprising that, despite of sharing this molecular mech anism, only dapsone shows anti-leprosy activity in vivo. The study was accomplished using molecular mechanics (SYBYL) and semiempirical meth ods (MOPAC). The calculations of aromaticity, charges, protonation by MOPAC, and of lipophilicity by our empirical program LIPOP(hilicity) g ive evidence that dapsone is more lipophilic (log P values 0.97) than sulfanilamide (-0.67). The extremely lipophilic cell wall of Mycobacte rium leprae contributes to the surprising difference in anti-leprosy a ctivity. Sulfonamides are more or less deprotonated (45 to 99 %) at ph ysiological pH units, whereas dapsone is totally undissociated. This r esults in different permeability rates into the bacterial cells in viv o. Compared to other sulfones and sulfonamides. the unique combination of high lipophilicity and low ionic dissociation favors anti-leprotic potency in dapsone. On principle, amide groups do not hinder activity , but cause acidity and subsequently dissociation.