Boosting Antifungal Efficacy against Magnaporthe oryzae via C═C Bond Modification in SDHI Tails

Succinate dehydrogenase inhibitors (SDHIs) are crucial fungicides, yet major commercial SDHIs exhibit suboptimal efficacy against the devastating rice blast pathogen Magnaporthe oryzae. This work introduces an alkene linker in the hydrophobic tail region of SDHIs through chain elongation and affords a library of 32 novel stereoisomeric compounds. This structural modification was predicated on the hypothesis that exploiting configurational isomerism (E vs Z) could optimize the spatial arrangement for enhanced binding. Indeed, the alkene-functionalized SDHIs demonstrated significantly enhanced activity against M. oryzae, with the most potent compound achieving 93.3% inhibition at 50 μM, substantially surpassing boscalid and fluxapyroxad. Critically, (E)-isomers consistently outperformed their (Z)-isomer. Enzyme kinetics confirmed this stereochemical advantage: the lead (E)-3 displayed potent SDH inhibition (IC₅₀ = 0.54 μM) 17-fold lower than that of fluxapyroxad (IC₅₀ = 9.50 μM). Molecular docking and molecular dynamics simulations revealed that the (E)-isomer has a superior binding affinity, attributed to optimal π-π stacking enabled by its alkene geometry. This study highlights alkene linker introduction and stereochemical optimization as a powerful strategy for developing next-generation M. oryzae SDHIs.