Discovery of Novel Pyrazole-4-Carboxamide and Aromatic Carboxamide Derivatives Containing a Trans-2-(Trifluoromethyl)cyclopropyl Moiety as Potential SDHIs

Abstract

A series of racemic pyrazole-4-carboxamide and aromatic carboxamide derivatives bearing a trans-2-(trifluoromethyl)cyclopropyl moiety were designed and synthesized as potential succinate dehydrogenase inhibitors (SDHIs). The compounds were evaluated for their in vitro and in vivo antifungal activities. Compound 10h showed potent activity against Rhizoctonia solani and Pyricularia oryzae, with EC50 values of 0.04 and 1.59 mg/L, respectively. At 5 mg/L, 10h provided 77.8% control of rice sheath blight and 88.9% control of soybean rust, outperforming fluxapyroxad and boscalid. It inhibited succinate dehydrogenase (SDH) with an IC50 value of 11.4 μM, compared with 14.5 μM for fluxapyroxad. Molecular docking and molecular dynamics simulations suggested that 10h may bind to SDH in a manner similar to that of fluxapyroxad. Compound 10h also showed lower acute toxicity to zebrafish embryos than fluxapyroxad. These results identify 10h as a promising lead for further optimization of trifluoromethylcyclopropyl-containing SDHIs.