New 5,6-dihydrobenzo[h]quinoline derivatives as potential demethylase inhibitors (DMIs): design, synthesis, activity...

Bipolaris maydis is a serious plant fungus and strongly affects the yield and quality of crops. The main control strategy is the employment of fungicides. To research efficient fungicide with novel structure, a series of novel 5,6-dihydrobenzo[h]quinoline derivatives were designed and synthesized.

Thirty-six novel 5,6-dihydrobenzo[h]quinoline analogues were designed and synthesized. The assay results showed that most compounds exhibited significant fungicidal activity against Pyricularia oryzae, Bipolaris maydis, Sclerotinia sclerotiorum, Penicillium digitatum and Valsa mali at 16 μg mL^-1. Compounds 4 h, 5e, 6a and 6b showed better antifungal activity than fluquinconazole against B. maydis. Their half maximal effective concentration (EC₅₀) values were 0.732, 0.283, 0.529, 0.644 and 0.826 μg mL^-1, respectively. Furthermore, the bioactive compounds were determined against sterol 14α-demethylase (CYP51). The results indicated that they displayed prominent inhibiting activities, 4 h, 5e, 6a and 6b also had better inhibitory activities than fluquinconazole against CYP51. Their half maximal inhibitory concentration (IC₅₀) values were 0.840, 0.315, 0.601, 0.750 and 1.018 μg mL^-1, respectively. The fluorescent quenching tests of proteins indicated that the quenching patterns of compounds 5e and 6a were analogous to fluquinconazole. The molecular dynamics (MD) simulations indicated that compound 5e possessed stronger affinity than fluquinconazole to CYP51.

The results of the present study displayed that novel 5,6-dihydrobenzo[h]quinoline derivatives could be one scaffold of potential CYP51 inhibitor and will provide some valuable information for the research and development of new fungicides. © 2024 Society of Chemical Industry.