Design, synthesis, and mechanism study of novel isoquinoline derivatives containing an oxime moiety as antifungal agents.

A series of novel isoquinoline derivatives 5a-5 s incorporating bioactive amide and oxime ester moieties were rationally designed and synthesized based-on isoquinoline alkaloid scaffolds through pharmacophore splicing strategy. Their structures were verified by H NMR, C NMR, IR and HRMS. The fungicidal bioassay indicated that most of the target compounds showed good to excellent inhibitory activity against five phytopathogenic fungi in vitro at a concentration of 50 mg/L. Notably, compounds 5 l and 5q exhibited excellent fungicidal activity against S. sclerotiorum with EC values reached 8.27 and 8.18 mg/L, respectively, which were comparable to boscalid (8.03 mg/L). 5q exhibited 100% protective and 73.87% curative efficacy against S. sclerotiorum on Brassica napus L. leaves at 100 mg/L. Particularly, compound 5q exhibits potent inhibitory effect against Succinate dehydrogenase (SDH) of S. sclerotiorum with IC of 5.05 uΜ. Furthermore, SDH activity assays and molecular docking analyses demonstrated that 5q can interact with SDH in a variety of ways. These results provide substantial insight for the development of novel natural-derived isoquinoline derivatives as potential antifungal agents.