One-Pot Synthesis of Chiral Succinate Dehydrogenase Inhibitors and Antifungal Activity Studies.

Abstract

In this work, a series of novel chiral succinate dehydrogenase inhibitors (SDHIs) are synthesized through a one-pot Rh-catalyzed asymmetric hydrogenation-condensation strategy. This method exhibits high efficiency (up to 1000 Ton, 94% yield over two steps), high stereoselectivity (up to 99% ee), and broad substrate scope (68 examples in total), providing a superior pathway for the synthesis of such chiral fungicides. Mechanistic studies indicate that the amino group at the 2-position of the phenyl ring acts as an activating group, enhancing the reactivity and stereoselectivity control of the reaction. Furthermore, these molecules exhibit broad-spectrum and highly effective antifungal biological activity. Notably, enantiomers show significant differences in both in vitro and in vivo fungi-inhibiting experiments. Especially, (S)-5f showcases an antifungal activity against Botrytis cinerea (EC₅₀ = 0.48 µm) that is much higher than that of its R enantiomer (EC₅₀ = 36.7 µm). Molecular docking calculations, molecular dynamic simulation, enzyme activity assays, and ligand-target interaction experiments demonstrate that (S)-5f (ΔG_MM-PBSA = -18.86 kcal mol^-1, K_D = 6.04 µm) inhibits succinate dehydrogenase more effectively than its R enantiomer (ΔG_MM-PBSA = -13.01 kcal mol^-1, K_D = 8.5 µm). Moreover, the two enantiomers have significantly different effects on spore germination and the destruction of fungal phenotype.