Synthesis and Antifungal Activities of Perillyl Alcohol Based 1,3,4-Thiadiazole-Thioether Compounds

A series of 33 perillyl alcohol based 1,3,4-thiadiazole-thioether compounds were designed and synthesized through active substructure splicing. Their structures were confirmed by ¹H NMR, ¹³C NMR, and HRMS, and their antifungal activities were evaluated in vitro. At a concentration of 50 mg/L, the target compounds exhibited varying inhibitory activities against Gibberella zeae (G. zeae), Botrytis cinerea, Rhizoctonia solani (R. solani), Rhizoctonia cerealis (R. cerealis), and Physalospora piricola (P. piricola). Among these, compound V15 (R = 3-FC₆H₄) demonstrated the strongest effects against G. zeae, R. solani, R. cerealis, and P. piricola, with inhibition rates of 77.8%, 67.3%, 83.9%, and 86.1%, respectively. Notably, its activity against G. zeae (77.8%) surpassed that of the positive control chlorothalonil (73.1%), and its activity against P. piricola (86.1%) was comparable to that of chlorothalonil (89.3%). A preliminary three-dimensional quantitative structure-activity relationship (3D-QSAR) model for R. cerealis inhibition was established using comparative molecular field analysis (CoMFA), yielding a reliable model (r² = 0.991, q² = 0.547).