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

Asian soybean rust (Phakopsora pachyrhizi) 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 FM-678 demonstrated exceptional efficacy against P. pachyrhizi with an EC50 of 0.14 mg·L-1, representing a 3-fold improvement over commercial flufenoxadiazam. FM-678 showed selective activity against rust pathogens, maintaining 30% control of Puccinia triticina 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 FM-678 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. FM-678 represents a promising candidate for sustainable soybean rust management with a novel mode of action.