New Methyl and Ethyl Gallate Esters Linked Chlorinated Benzoyl Derivatives as Anti-Candida albicans Agents: Isolation, Semi-Synthesis, In Vitro and In Silico Studies.

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 (∆Gbind) 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.