Synthesis and Antifungal Evaluation of Isoquinoline-3-amide Derivatives Containing a Phenoxypyridine Moiety for Plant...

To discover novel green antifungal candidates, 20 3-acylaminoisoquinoline derivatives were designed and synthesized by introducing the active fragment phenoxypyridine. Their structures were verified by ¹H NMR, ¹³C NMR, and HRMS. The structure of compound X9 was further confirmed via X-ray crystallography. Their antifungal activities against five phytopathogenic fungi were evaluated to develop isoquinoline-based antifungal agents. Among them, compound X6 demonstrated significant antifungal activity against Botrytis cinerea with an EC₅₀ value of 7.55 µg/mL. In vivo assays revealed that compound X6 exhibited strong protective and curative efficacy against B. cinerea with rates of 77.86% and 45.45% at a concentration of 100 µg/mL. Molecular docking studies confirmed that isoquinoline amide compounds possess strong binding affinity to succinate dehydrogenase (SDH). Molecular dynamics (MD) simulations revealed that compound X6 has better pocket spatial compatibility and more stable binding interactions with SDH than boscalid. Furthermore, SDH activity assays showed compound X6 inhibited SDH activity by 66.7% at 4 EC₅₀ concentration, which was comparable to that of the boscalid (75.85%). These findings demonstrated that isoquinoline derivatives incorporating the phenoxypyridine fragment possess potent fungicidal properties for crop safety, with compound X6 emerging as a promising candidate for a novel SDH inhibitor.