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 againstPhysalospora piricola. Compounds5b(R =o-CH3Ph),5i(R =o-Cl Ph),5v(R =m,p-OCH3Ph) and5x(R =α-furyl) had inhibition rates of 93.3%, 79.4%, and 79.4%, respectively, againstP. piricola, much better than that of the positive control chlorothalonil. Compounds5v(R =m,p-OCH3Ph) and5g(R =o-Cl Ph) held inhibition rates of 82.4% and 86.5% againstCercospora arachidicolaandGibberella zeae, respectively, much better than that of the commercial fungicide chlorothalonil. Compound5b(R =o-CH3Ph) displayed antifungal activity of 90.5% and 83.8%, respectively, againstColleterichum orbicalareandFusarium oxysporumf. sp.cucumerinum. Compounds5m(R =o-I Ph) had inhibition rates of 88.6%, 80.0%, and 88.0%, respectively, againstF. oxysporumf. sp.cucumerinu,Bipolaris maydisandC. orbiculare. Furthermore, compound5b(R =o-CH3Ph) showed the best and broad-spectrum antifungal activity against all the tested fungi. To design more effective antifungal compounds againstP. piricola, 3D-QSAR analysis was performed using the CoMFA method, and a reasonable 3D-QSAR model (r2= 0.991,q2= 0.514) was established. The simulative binding pattern of the target compounds with cytochrome P450 14α-sterol demethylase (CYP51) was investigated by molecular docking.Keywords:menthol;1,2,4-triazole-thioether;antifungal activity;3D-QSAR;molecular docking