Synthesis of N-acylsulfonamide chromone derivatives as efficient anti-Candida albicans agents

Abstract

32 novel N-acylsulfonamide chromone derivatives were designed and synthesized. Their properties were theoretically investigated using Density Functional Theory (DFT) calculations at the B3LYP/6–311++G(d,p) level. Frontier molecular orbital (FMO) analysis highlighted charge transfer capabilities, while electrostatic potential (ESP) pinpointed nucleophilic/electrophilic active sites governing molecular interactions. Using techniques from cell biology and optical imaging, we explored the antifungal mechanisms of these synthesized compounds against Candida albicans. Experimental results showed that N-acylsulfonamide chromones disrupt the permeability of the Candida albicans cell membrane and the integrity of the cell wall, subsequently affecting the normal energy metabolism of the cells and leading to fungal cell death. Moreover, molecular docking and molecular dynamics simulations revealed stable binding of lead compounds to Candida albicans CYP51 (Sterol 14α-demethylase), with binding energies (−10.9 to −12.1 kcal/mol) and low RMSD fluctuations (<1.0 Å). In conclusion, N-acylsulfonamide chromones show great potential as candidates for the development of new antifungal drugs to treat Candida albicans infections.