Advancements in Fungicidal Chemistry: FM-678─A Highly Promising Fungicidal Candidate for Combating Asian Soybean Rust

Asian soybean rust (<i>Phakopsora pachyrhizi</i>) threatens global soybean production, with existing fungicides increasingly compromised by resistance. We designed and synthesized 52 novel 5-(trifluoromethyl)-1,2,4-oxadiazole derivatives containing malononitrile moieties targeting histone deacetylase (HDAC) as an innovative antifungal mechanism. Lead compound <b>FM-678</b> demonstrated exceptional efficacy against <i>P. pachyrhizi</i> with an EC₅₀ of 0.14 mg·L^-1, representing a 3-fold improvement over commercial flufenoxadiazam. <b>FM-678</b> showed selective activity against rust pathogens, maintaining 30% control of <i>Puccinia triticina</i> at 0.391 mg·L^-1. Molecular docking revealed enhanced zinc chelation through the oxadiazole ring and critical hydrogen bonds with His158, Cys169, and Gly330 residues. DFT calculations showed <b>FM-678</b> possessed the smallest HOMO-LUMO energy gap (0.23155 a.u.), correlating with superior bioactivity. Structure-activity relationships identified essential features: preserved amide linkage, small cyclic acyl substituents (especially three-membered rings), and meta-positioning on benzoyl groups. <b>FM-678</b> represents a promising candidate for sustainable soybean rust management with a novel mode of action.