Computational study of substituent effects on the acidity, toxicity and chemical reactivity of bacteriostatic sulfonamides

Relationships among physicochemical properties, the chemical structure and antibacterial activity of sulfonamides have not been completely explicated yet. Nevertheless, from a therapeutics and prodrugs design point of view, a substituent group can modify the electronic structure, the physicochemical features and chemical reactivity which are critical for the biological activity. In this work, we analyze the substituent effects on the physicochemical properties, toxicity, chemical reactivity and its relation with the bacteriostatic activity of selected sulfonamides by means of DFT-M06-2X calculations in aqueous solution, using quantum chemical and docking descriptors. A correlation between the theoretical acidity and the pKa experimental values has been found. The more active sulfonamides have a larger acidity. The acidity increases with electron-withdrawing substituents. The main reactivity takes place on N4 atoms linked to aromatic ring, and in the SO₂NH moiety, which are influenced by substituents. Docking descriptors showed binding affinities between sulfonamides and target receptor, the dihydropteroate synthase (DHPS).