Acylpiperidine Formononetin Derivatives as Antimicrobial Lead Compounds: Activity and Preliminary Mode-of-Action Studies

Abstract

Global agricultural production relies heavily on chemical pesticides, leading to resistance, residues, and pollution, threatening sustainable agriculture. There is an urgent need to develop novel antimicrobial agents from low-toxicity, easily degradable natural products. Using formononetin as a lead compound, acylpiperidine-containing derivatives were synthesized and evaluated against one oomycete, seven plant pathogenic fungi, and four pathogenic bacteria. C25 exhibited superior inhibitory effects against Phytophthora capsici and Xanthomonas oryzaepv.oryzae, with EC50 values of 3.38 and 1.67 μg/mL, respectively, outperforming azoxystrobin and thiodiazole copper. Preliminary mode-of-action studies, including cytoplasmic leakage, membrane permeability, and defense enzyme analyses, provided initial insights into its antimicrobial properties. Seed germination assays showed no obvious phytotoxicity, and zebrafish embryos developed normally at concentrations up to 50 μg/mL, whereas sublethal effects appeared at higher concentrations. Molecular docking and density functional theory calculations provided preliminary insights into possible interactions and electronic characteristics. C25 represents a promising lead for botanical-source antimicrobial agrochemicals.