Synthesis, biological evaluation, in-silico ADME and molecular docking studies of novel chalcone derivatives as promising antifungal agents

A series of differently substituted chalcones, Ar–C(O)CH=CH–Ar′ ( 1 – 17 ), were synthesized and characterized using FT-IR, 1 H NMR, 13 C NMR, and mass spectrometry. All the compounds were screened for antifungal activity against the pathogenic yeast Candida albicans by agar diffusion assay at concentrations of 0.5, 1, and 2 mg mL −1 . Eight compounds ( 2 , 3 , 7 , 8 , 11 , 12 , 16 , and 17 ) demonstrated significant inhibitory activities, producing inhibition zones of 12–18 mm at 1–2 mg mL −1 . No inhibition was observed at 0.5 mg mL −1 for any compound except 8 , which showed the highest overall activity, yielding inhibition zones of 11, 15, and 18 mm at 0.5, 1, and 2 mg mL −1 , respectively. To investigate their mechanism of action, molecular docking studies were performed, which verified the ability of these compounds to bind to the C. albicans N -myristoyltransferase active site (PDB ID: 1IYL) through hydrogen-bond interactions involving key residues such as Gln-226, Cys-393, and Asn-392. Docking simulations analysis identified compound 3 as the most promising inhibitor, showing stable binding interactions (−11.71 kcal mol −1 ) with 1IYL, which suggests its potential as an antifungal therapeutic target. In addition, in-silico absorption, distribution, metabolism, and excretion (ADME) profiling predicted generally acceptable drug-like properties for these derivatives, including favorable topological polar surface area (TPSA) values and oral bioavailability, with low predicted toxicity for most derivatives. Overall, the combined in-vitro and in-silico results identify compounds 3 , 7 , 8 , and 16 as the most promising candidates for further antifungal optimization and mechanistic evaluation.