Novel Naphthyl and Phenyl Maleimide Derivatives: Molecular Design, Systematic Optimization, Antifungal Evaluation, and Action Mechanism

A systematic optimization strategy, as an effective screening approach for new antifungal compounds, was implemented to rationally construct novel naphthyl and phenyl maleimide derivatives. The structures of molecules <b>A32</b> and <b>B6</b> were further confirmed by single-crystal X-ray diffraction. The <i>in vitro</i> antifungal activity evaluation showed that the target compound <b>A32</b> obtained by the structure optimization exhibited excellent inhibition (EC₅₀ = 0.59 μg/mL) against <i>Rhizoctonia solani</i>, which was better than the control agent dimethachlone (1.21 μg/mL). Further evaluation by <i>in vivo</i> experiments on rice leaves and potted rice plants against <i>R. solani</i> at 200 μg/mL showed that <b>A32</b> possessed an outstanding protective efficiency compared to dimethachlone. The mycelium morphology observation by SEM indicated that <b>A32</b> (25 μg/mL) severely damaged the surface structure of the mycelium, which was in accordance with the increased result of the cell membrane permeability assay. MD simulations and molecular docking analysis revealed that compounds <b>A1</b> and <b>A32</b> have a similar binding mode in the active pocket of plasma membrane H⁺-ATPases (PMA1) as the reference fungicide fluoroimide. In particular, there were more hydrogen bonds in the protein complex of <b>A32</b> than in the protein complexes of <b>A1</b> and fluoroimide. This research on constructing novel naphthyl and phenyl maleimide derivatives by a systematic optimization strategy provides a practical way to find new antifungal leads, thereby developing novel fungicides.