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 EC 50 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.