Synthesis, Antifungal Activity, and 3D-QSAR Study of Novel Nopol-Derived 1,3,4-Thiadiazole-Thiourea Compounds.

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 Fusarium oxysporum f. sp. cucumerinum , Cercospora arachidicola , Physalospora piricola , Alternaria solani , Gibberella zeae , Rhizoeotnia solani , Bipolaris maydis , and Colleterichum orbicalare at 50 µg/mL. All the target compounds exhibited better antifungal activity against P. piricola , C. arachidicola , and A. solani . Compound 6j (R = m , p -Cl Ph) showed the best broad-spectrum antifungal activity against all the tested fungi. Compounds 6c (R = m -Me Ph), 6q (R = i -Pr), and 6i (R = p -Cl Ph) had inhibition rates of 86.1%, 86.1%, and 80.2%, respectively, against P. piricola , much better than that of the positive control chlorothalonil. Moreover, compounds 6h (R = m -Cl Ph) and 6n (R = o -CF ₃ Ph) held inhibition rates of 80.6% and 79.0% against C. arachidicola and G. zeae , respectively, much better than that of the commercial fungicide chlorothalonil. In order to design more effective antifungal compounds against A. solani , 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 ( r ² = 0.992, q ² = 0.753) has been established. Furthermore, some intriguing structure-activity relationships were found and are discussed by theoretical calculation.