New Methyl and Ethyl Gallate Esters Linked Chlorinated Benzoyl Derivatives as Anti-Candida albicans Agents:...

Fungal infections caused by pathogenic fungi, particularly Candida albicans, range from oral thrush to severe systemic infections, especially in immunocompromised individuals. To address this, we employed a single-step reaction procedure to esterify methyl gallate (MG) and ethyl gallate (EG), isolated from the EtOAc-soluble fraction of the hydromethanolic leaf extract of Vachellia nilotica L. (Fabaceae), using substituted benzoyl chlorides. The structures of the synthesized ester analogs (MG1-MG4 and EG1-EG4) were characterized using UV, FT-IR, NMR, and mass spectrometry. Among them, MG1 showed the highest C. albicans inhibition (83.8%). Molecular docking analysis against C. albicans 14α-demethylase (CaCYP51) revealed a binding free energy (∆G_bind) of -33.08 kcal/mol for MG1, which is comparable to that of fluconazole (-36.91 kcal/mol) and consistent with the in vitro results. MD simulation demonstrated good stability of complex-MG1 throughout the simulation, with fluctuations remaining below 4.0 Å. In the active site, fluconazole formed a hydrogen bond with T267, while MG1 interacted with Y461 via hydrogen bonding. Given the close alignments between in vitro and in silico results, MG1 is identified as a potential C. albicans inhibitor, although alternative inhibition mechanisms may also be involved. However, further research, including in vivo studies and toxicity evaluations, is required.