Discovery of Novel Carboxamide Derivatives Containing Biphenyl Pharmacophore as Potential Fungicidal Agents Used for Resistance Management

Natural products are one of the main sources of drug and agrochemicals discovery. Biphenyls skeleton are ubiquitous structures in many classes of natural products, which indicate extensive biological activities. So, in order to investigate the potential applications for natural biphenyl derivatives, a series of novel carboxamide derivatives with diverse substituent patterns were designed and synthesized based on active pharmacophore from natural biphenyl lignans, and their in vitro antifungal activities against several typical plant pathogens belonging to oomycetes, ascomycete, deuteromycetes, and basidiomycetes were fully investigated. The highly potential compounds were further tested in vivo assay against Botrytis cinerea Pers. of cucumber to demonstrate a practical application for controlling common plant diseases, which indicated four compounds could effectively control the resistant strains of carbendazim, rutamycin, and pyrazolidide. The potential modes of action for compound B12 against B. cinerea were also explored using molecular docking, microscopic technology, and label-free quantitative proteomics analysis. The results show that compound B12 may be a potential novel fungicidal agent used for gray mold resistance control, which can influence the protein synthesis of B. cinerea. These findings can provide a certain theoretical basis for the development of novel biphenyl derivatives as potential green antifungal agents.