Scaffold Hopping-Driven Discovery of Novel Thioether Fungicides: Design, SAR, and Computational Insights into Structure-Activity Relationships.

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.