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 f. sp. , , , , , , , and at 50 µg/mL. All the target compounds exhibited better antifungal activity against , , and . Compound (R = , -Cl Ph) showed the best broad-spectrum antifungal activity against all the tested fungi. Compounds (R = -Me Ph), (R = -Pr), and (R = -Cl Ph) had inhibition rates of 86.1%, 86.1%, and 80.2%, respectively, against , much better than that of the positive control chlorothalonil. Moreover, compounds (R = -Cl Ph) and (R = -CF Ph) held inhibition rates of 80.6% and 79.0% against and , respectively, much better than that of the commercial fungicide chlorothalonil. In order to design more effective antifungal compounds against , 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 ( = 0.992, = 0.753) has been established. Furthermore, some intriguing structure-activity relationships were found and are discussed by theoretical calculation.