To discover potent antifungal molecules with new and distinctive structures, 20 novel L-carvone-derived 1,3,4-oxadiazolethioether compounds 5 a-5 t were synthesized through multistep reaction of L-carvone, and their structures were confirmed by FT-IR, 1 H-NMR, 13 C-NMR, and HR-MS. The antifungal activities of compounds 5 a-5 t were preliminarily tested by in vitro method, and the results indicated that all of the title compounds displayed certain antifungal activities against the eight tested plant fungi, especially for P. piricola. Among them, compound 5 i (R = p-F) with the most significant antifungal activity deserved further study for discovering and developing novel natural product-based antifungal agents. Moreover, two molecular simulation technologies were employed for the investigation of their structure-activity relationships (SARs). Firstly, a reasonable and effective 3D-QSAR model was established by the comparative molecular field (CoMFA) method, and the relationship of the substituents linked with the benzene rings and the inhibitory activities of the title compounds against P. piricola was elucidated. Then, the binding mode of compound 5 i (R = p-F) and its potential biological target (CYP51) was simulated by molecular docking, and it was found that compound 5 i could readily bind with CYP51 in the active site, and the ligand-receptor interactions involved three hydrogen bonds and several hydrophobic effects.

For exploring new natural product‐based leading compounds with antifungal activity, 15 novel 3‐carene‐derived 4‐substituted phenyl‐1,2,4‐triazolinthiones 7a∼7o bearing gem‐dimethylcyclopropane moiety were synthesized and structurally characterized by UV/VIS, FT‐IR, 1H‐NMR, 13C‐NMR, ESI‐MS and elemental analysis. The preliminary bioassay at 50 μg/mL showed that all of the target compounds exhibited certain in vitro inhibitory activities against the eight tested fungi, in which compound 7g (R=m, p‐Cl) displayed better inhibition activity (85.0 %) against P. piricola than that of the positive control Chlorothalonil. Furthermore, a reasonable and effective 3D structure of phytofungal CYP51 was constructed by homology modeling. Molecular docking study revealed that the total scores of all the target compounds were higher than that of Prothioconazole. In addition, it was found that compound 7g could readily embed into the binding site, and therein shared similar interactions with the case of Prothioconazole. Thus, compound 7g deserved further study as an antifungal leading compound.