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Scaffold Hopping-Driven Discovery of Novel Thioether Fungicides: Design, SAR, and Computational Insights into
Yuandong Liu1, Jialin Ye1, Yuxin Huang1
1National-Local Joint Engineering Laboratory for Development of Boron and Magnesium Resources and Fine Chemical Technology, Liaoning Province Key Laboratory of Green Functional Molecular Design and Development, Shenyang Key Laboratory of Targeted Pesticides, Institute of Functional Molecules, Shenyang University of Chemical Technology, Shenyang110142, China.
Abstract:
Sixty novel 5-(trifluoromethyl)-1,2,4-oxadiazole derivatives were designed by scaffold hopping from the diamide lead 6n and synthesized to examine ether, thioether, and sulfoxide linkers. Greenhouse assays against Phakopsora pachyrhizi identified FM-12818 (B5) as a leading thioether derivative, with an EC50 of 0.45 mg·L-1, comparable to flufenoxadiazam (0.49 mg·L-1). FM-12818 also provided 80% control of Puccinia triticina at 0.391 mg·L-1 under the tested conditions. Docking to a human HDAC4 surrogate and DFT calculations suggested a putative zinc-binding orientation and linker-dependent electronic differences, including a possible π-sulfur contact. These computational observations generate hypotheses for the structure-activity relationship but do not establish HDAC inhibition or a distinct mode of action. FM-12818, therefore, represents a potent greenhouse lead for further target validation, field efficacy, and safety studies.