INVESTIGATION OF SULFONAMIDES AND THEIR ANALOGUES AS ANTIFUNGAL AGENTS

Abstract

The rising incidence of fungal infections, together with increasing resistance to available antifungal drugs, represents a growing healthcare concern and underscores an urgent need for novel antifungal therapies with improved efficacy.Sulfonamides represent one of the oldest classes of synthetic antimicrobial agents. Their activity stems from the inhibition of folate biosynthesis; however, recent studies have revealed "non-classical" mechanisms of action, including interference with peptidoglycan biosynthesis and inhibition of various enzymes. These findings support the revival of sulfonamides as versatile scaffolds for developing new antimicrobials targeting resistant pathogens.1 Although not originally considered as antifungal agents, sulfonamides have demonstrated antifungal properties, synergy with azoles, and ability to disrupt biofilms.In this study, we report design and synthesis of a pilot series of molecules combining 4-aminobenzenesulfonamide and salicylic moieties (1), aiming to identify lead compounds with potent antifungal action. The synthetic route involved three main steps: (1) synthesis of sulfonamides or their analogues (e.g., sulfones), if commercially unavailable; (2) condensation with appropriate salicylic derivative to form imines; and (3) further modification of imines (double bond reduction, esterification etc.).All final compounds as well as intermediates were evaluated for antimycobacterial, antibacterial, and antifungal activities, as well as cytotoxicity. The results revealed significant antifungal activity across the series, with MIC values starting at 1 uM against both yeasts and molds. Several compounds also showed mild inhibition of Gram-positive cocci (>=62.5 uM). Notably, antifungal activity was retained also against drug-resistant clinical isolates and Candida auris. The most potent compound, a derivative of sulfameter, was selected for further advanced studies.