Molecular modeling study on dapsone and sulfonamides comparing structures and properties with respect to anti-leprosy activity

Despite the very close structural relationship between dapsone (4,4'-diaminodiphenyl sulfone, 4,4' sulphonyldianiline, diaphenyl sulphone, DDS) and sulfanilamide (p-aminobenzene sulfonamide), being the prototype of all other sulfonamides, only dapsone shows remarkable efficient pharmacological 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 PABA. It is most surprising that, despite of sharing this molecular mechanism, only dapsone shows anti-leprosy activity in vivo. The study was accomplished using molecular mechanics (SYBYL) and semiempirical methods (MOPAC). The calculations of aromaticity, charges, protonation by MOPAC, and of lipophilicity by our empirical program LIPOP(hilicity) give evidence that dapsone is more lipophilic (log P values 0.97) than sulfanilamide (-0.67). The extremely lipophilic cell wall of Mycobacterium leprae contributes to the surprising difference in anti-leprosy activity. Sulfonamides are more or less deprotonated (45 to 99 %) at physiological pH units, whereas dapsone is totally undissociated. This results in different permeability rates into the bacterial cells in vivo. 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.