CoMFA Directed Molecular Design for Significantly Improving Fungicidal Activity of Novel [1,2,4]-Triazolo-[3,4- b ][1,3,4]-thiadizoles.

Target based molecular design via the aid of computation is one of the most efficient methods in the discovery of novel pesticides. Here, a combination of the comparative molecular field analysis (CoMFA) and molecular docking was applied for discovery of potent fungicidal [1,2,4]-triazolo-[3,4- b ][1,3,4]-thiadiazoles. Bioassay results indicated that the synthesized target compounds 3a , 3b , and 3c exhibited good activity against Alternaria solani , Botrytis cinerea , Cercospora arachidicola , Fusarium graminearum , Physalospora piricola , Rhizoctonia solani , and Sclerotinia sclerotiorum with an EC 50 value falling between 0.64 and 16.10 μg/mL. Specially, 3c displayed excellent fungicidal activity against C. arachidicola and R. solani, which was 5 times more potent than the lead YZK-C22 . The enzymatic inhibition assay and fluorescence quenching analysis with R. solani pyruvate kinase (RsPK) showed a weaker binding affinity between RsPK and 3a , 3b , or 3c . Transcriptomic analyses showed that 3c exerted its fungicidal activity by disrupting steroid biosynthesis and ribosome biogenesis in eukaryotes. These findings support that 3c is a promising fungicide candidate, and a fine modification from a lead may lead to a totally different mode of action.