Discovery of Thiazole-5-Carboxamide Derivatives Containing Diphenyl Ether Fragments as Potential Succinate Dehydrogenase Inhibitors

Abstract

Succinate dehydrogenase inhibitors (SDHIs) have become one of the fastest-growing categories in the fungicide market and are widely utilized for crop protection in agricultural production. Currently, guided by the imperative of cost reduction and efficiency enhancement, the replacement of biphenyl fragments in SDHIs with cost-effective diphenyl ether fragments has emerged as an innovative strategy for developing novel, highly efficient, and broad-spectrum fungicides. Based on the above structural features, 45 thiazole-5-carboxamide derivatives containing diphenyl ether fragments (potentially targeting fungal SDH) were designed and evaluated for their antifungal effects against Rhizoctonia solani, Sclerotinia sclerotiorum, Alternaria alternata, and Alternaria solani. Notably, the in vitro EC₅₀ value of compound IIIe against R. solani was 0.009 mg/L, exhibiting significantly greater potency than thifluzamide (0.039 mg/L), boscalid (1.849 mg/L), fluxapyroxad (0.049 mg/L), and carboxin (0.146 mg/L), and proving comparable to that of the novel SDHIs fungicide flubeneteram (0.008 mg/L). Concurrently, compound IIIe demonstrated high efficacy in controlling rice sheath blight through detached leaf and pot experiments. Further investigations into fungal SDH inhibition, respiratory suppression, mitochondrial membrane potential detection, molecular docking, cell cytotoxicity, scanning electron microscopy, and transmission electron microscopy analysis confirmed the practical value of compound IIIe as a potential SDHI. The present results provide an indispensable complement for the structural optimization of antifungal leads to the targeting of SDH.