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 EC₅₀ 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.

[1,2,4]-triazolo-[3,4-b][1,3,4]-thiadiazole; computer-aided drug design; fungicidal activity; molecular docking; transcriptomic.