Natural Furan-Carboxylic Acid (HHCA) and Its Derivatives: Synthesis, Characterization, Bioevaluation, and Structure–Activity Relationships as Potential Fungicidal Agents

The exploration of natural products as lead scaffolds continues to serve as a valuable strategy for the development of novel antifungal agents. In this investigation, we focused on the natural furanoid compound 2-heptyl-5-hexylfuran-3-carboxylic acid (HHCA) and designed and synthesized four distinct series of multisubstituted furan carboxylic acid derivatives. Comprehensive structural characterization and biological evaluation were performed for all 48 compounds. In vitro antifungal screening against eight prevalent plant pathogens revealed that some of these derivatives exhibited significant inhibitory effects against <i>Botrytis cinerea</i> and <i>Sclerotinia sclerotiorum</i>. Structure-activity relationship analysis demonstrated that peptide-containing derivatives showed superior antifungal potency compared with their hydrazide, amide, and ester counterparts. The most promising candidate compound <b>5g</b> was further evaluated for its in vivo efficacy against two plant pathogens, <i>S. sclerotiorum</i> and <i>B. cinerea</i>, indicating potent antifungal activity with EC₅₀ values of 17.14 μg/mL and 19.63 μg/mL, respectively. Notably, these values were significantly lower than those of the natural product HHCA with an enhanced antifungal potency. These findings highlight the practical potential of compound <b>5g</b> as a novel antifungal agent for agricultural applications. Mechanistic investigations employing microscopic analysis, molecular docking simulations, and density functional theory (DFT) calculations provided insights into the putative mode of action of <b>5g</b>, particularly regarding its interaction with succinate dehydrogenase (SDH). These findings establish a foundation for the rational development of HHCA-derived furan derivatives as novel SDH-targeting fungicidal agents.