Synthesis, Antifungal Activity, 3D-QSAR, and Molecular Docking Study of Novel Menthol-Derived 1,2,4-Triazole-thioether Compounds.

A series of novel menthol derivatives containing 1,2,4-triazole-thioether moiety were designed, synthesized, characterized structurally, and evaluated biologically to explore more potent natural product-based antifungal agents. The bioassay results revealed that at 50 μg/mL, some of the target compounds exhibited good inhibitory activity against the tested fungi, especially against . Compounds (R = -CH Ph), (R = -Cl Ph), (R = ,-OCH Ph) and (R = -furyl) had inhibition rates of 93.3%, 79.4%, and 79.4%, respectively, against , much better than that of the positive control chlorothalonil. Compounds (R = ,-OCH Ph) and (R = -Cl Ph) held inhibition rates of 82.4% and 86.5% against and , respectively, much better than that of the commercial fungicide chlorothalonil. Compound (R = -CH Ph) displayed antifungal activity of 90.5% and 83.8%, respectively, against and f. sp. . Compounds (R = -I Ph) had inhibition rates of 88.6%, 80.0%, and 88.0%, respectively, against f. sp. , and . Furthermore, compound (R = -CH Ph) showed the best and broad-spectrum antifungal activity against all the tested fungi. To design more effective antifungal compounds against , 3D-QSAR analysis was performed using the CoMFA method, and a reasonable 3D-QSAR model ( = 0.991, = 0.514) was established. The simulative binding pattern of the target compounds with cytochrome P450 14α-sterol demethylase (CYP51) was investigated by molecular docking.