Design, Synthesis, and Bioactivity Evaluation of Novel Indene Amino Acid Derivatives as Succinate Dehydrogenase Inhibitors

Succinate dehydrogenase inhibitors (SDHIs) represent one of the three predominant fungicide categories in contemporary agricultural markets, garnering an increasing level of research interest. Building upon our prior work utilizing aminocyclobutanecarboxylic acid as a linker, we designed and synthesized a novel series of indene amino acid derivatives to optimize hydrophobic interactions with the SDH enzyme. These derivatives demonstrated potent in vitro antifungal activity against <i>Rhizoctonia solani</i>, <i>Botrytis cinerea</i>, and <i>Sclerotinia sclerotiorum</i>, with compound <b>i19</b> exhibiting efficacy comparable to boscalid against all three pathogens. Structure-activity relationship analysis coupled with 3D-QSAR modeling revealed significant enzymatic inhibition enhancement, particularly in compound <b>i18</b>, which showed a 7.4-fold improvement in porcine heart SDH inhibition (IC₅₀ = 0.5026 μM) versus the parent structure (IC₅₀ = 3.7257 μM). Lipophilicity mapping and molecular docking simulations attribute this enhancement to indene fragment-induced optimization of hydrophobic pocket interactions. Scanning electron microscopy revealed analogous mycelial deformation patterns between <b>i19</b>-treated and fluxapyroxad-treated samples. Complementary DFT calculations and molecular electrostatic potential analysis further corroborated the proposed binding mode, establishing this indene amino acid scaffold as a promising lead structure for next-generation SDHI development.