Design, synthesis and mechanism study of novel natural-derived isoquinoline derivatives as antifungal agents

In screening for natural fungicidal leads, two series of novel 3-aryl-isoquinoline derivatives 8 and 9 were designed and synthesized based on sanguinarine, chelerythrine and berberine. Their structures were confirmed by 1D, 2D NMR and HRMS. Most of the title compounds showed medium to excellent antifungal activity in vitro at 50 mg/L, which were much more active than the lead of sanguinarine. Especially, 9f possessed the best effective against Alternaria solani (80.4%), Alternaria alternata (88.2%) and Physalospora piricola (93.8%). Furthermore, the EC50 of 9f (3.651 mg/L) against P. piricola was marginally better than chlorothalonil (3.869 mg/L). In vivo antifungal activity of 9f against P. piricola was studied on apples. The curative and protection results at the dosage of 50 and 100 mg/L showed as 70.45 ~ 81.67% and 64.96 ~ 80.34%, respectively, which were equal to that of chlorothalonil (80.30 ~ 86.67%, 73.08 ~ 76.92%). Molecular electrostatic potential and molecular docking analysis revealed that 9f was fully covered by positive potential contour, which was easier to interact with the negative amino acid resides of succinate dehydrogenase than 8f. 9f could be used as a novel antifungal lead compound for further study. Two series of novel isoquinoline derivatives 8, 9 containing 3-aryl were rational designed and synthesized based on quaternary isoquinoline alkaloids. The bioassay and interaction mechanism studies indicated that 9f should be considered as potential antifungal lead.