| Summary: | A series of novel nopol derivatives bearing the 1,3,4-thiadiazole-thiourea moiety were designed and synthesized by multi-step reactions in search of potent natural product-based antifungal agents. Their structures were confirmed by FT-IR, NMR, ESI-MS, and elemental analysis. Antifungal activity of the target compounds was preliminarily evaluated by in vitro methods against <i>Fusarium oxysporum</i> f. sp. <i>cucumerinum</i>, <i>Cercospora arachidicola</i>, <i>Physalospora piricola</i>, <i>Alternaria solani</i>, <i>Gibberella zeae</i>, <i>Rhizoeotnia solani</i>, <i>Bipolaris maydis</i>, and <i>Colleterichum orbicalare</i> at 50 µg/mL. All the target compounds exhibited better antifungal activity against <i>P. piricola</i>, <i>C. arachidicola</i>, and <i>A. solani</i>. Compound <b>6j</b> (R = <i>m</i>, <i>p</i>-Cl Ph) showed the best broad-spectrum antifungal activity against all the tested fungi. Compounds <b>6c</b> (R = <i>m</i>-Me Ph), <b>6q</b> (R = <i>i</i>-Pr), and <b>6i</b> (R = <i>p</i>-Cl Ph) had inhibition rates of 86.1%, 86.1%, and 80.2%, respectively, against <i>P. piricola</i>, much better than that of the positive control chlorothalonil. Moreover, compounds <b>6h</b> (R = <i>m</i>-Cl Ph) and <b>6n</b> (R = <i>o</i>-CF<sub>3</sub> Ph) held inhibition rates of 80.6% and 79.0% against <i>C. arachidicola</i> and <i>G. zeae</i>, respectively, much better than that of the commercial fungicide chlorothalonil. In order to design more effective antifungal compounds against <i>A. solani</i>, analysis of the three-dimensional quantitative structure–activity relationship (3D-QSAR) was carried out using the CoMFA method, and a reasonable and effective 3D-QSAR model (<i>r</i><sup>2</sup> = 0.992, <i>q</i><sup>2</sup> = 0.753) has been established. Furthermore, some intriguing structure–activity relationships were found and are discussed by theoretical calculation.
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