Discovery of Nitrogen-Containing Heterocyclic Chain Amide Derivatives as Novel Fungicidal Agents via Multicomponent Strategies

This study aimed to develop novel antifungal agents against plant pathogenic fungi. A series of nitrogen-containing heterocycle-directed linear bisamide compounds were designed and synthesized via an efficient multicomponent one-pot synthetic strategy. The structures were unambiguously characterized by NMR spectroscopy and ESI-MS analysis. Bioassay results demonstrated that most compounds exhibited superior antifungal efficacy against eight plant pathogenic fungi compared to the positive control boscalid at a 100 μg/mL concentration. Notably, selected compounds achieved remarkable inhibition rates exceeding 80% against S. sclerotiorum at the same concentration. Similar potency was observed against B. cinerea and P. capsici. Particularly intriguing was the exceptional activity of compound 4 (EC₅₀ = 4.37 μg/mL) against P. capsici, which significantly surpassed that of boscalid (EC₅₀ > 100 μg/mL). Mechanistic studies combining DFT calculations, molecular docking, and molecular dynamics simulations suggested these compounds might function as potential SDH inhibitors. Importantly, phytotoxicity evaluation revealed no observable adverse effects on maize and wheat growth, indicating favorable crop compatibility. This study establishes a framework for rational design of structurally novel SDH inhibitors that combine broad-spectrum antifungal potency with low phytotoxicity.