Synthesis, Antifungal Activity, and Molecular Docking Study of Novel 3-Carene-Derived 4-Substituted Phenyl-1,2,4-Triazolinthiones Bearing gem-Dimethylcyclopropane Moiety.

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, 1 H-NMR, 13 C-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.

Synthesis of Bioactive Compounds from 3-Carene (II): Synthesis, Antifungal Activity and 3D-QSAR Study of (Z)- and (E)-3-Caren-5-One Oxime Sulfonates.

A series of novel (Z)- and (E)-3-caren-5-one oxime sulfonates were designed and synthesized in search of potent antifungal agents. The structures of the intermediates and target compounds were confirmed by UV-Vis, FTIR, NMR, and ESI-MS. The in vitro antifungal activity of the target compounds was preliminarily evaluated against Cercospora arachidicola, Physalospora piricola, Alternaria solani, Rhizoeotnia solani, Bipolaris maydis and Colleterichum orbicalare at 50 µg/mL. The bioassay results indicated that the target compounds exhibited the best antifungal activity against P. piricola, in which compounds 4b, 4f, 4m, 4e, 4j, 4l, 4y, 4d, and 4p had excellent inhibition rates of 100%, 100%, 100%, 92.9%, 92.9%, 92.9%, 92.9%, 85.7%, and 85.7%, respectively, showing much better antifungal activity than that of the commercial fungicide chlorothanil. Both the compounds 4y and 4x displayed outstanding antifungal activity of 100% against B. myadis, and the former also displayed outstanding antifungal activity of 100% against R. solani. In order to design more effective antifungal compounds against P. piricola, the analysis of three-dimensional quantitative structure-activity relationship (3D-QSAR) was carried out using the CoMFA method, and a reasonable and effective 3D-QSAR model (r² = 0.990, q² = 0.569) has been established.