Rational Design and Synthesis of Potent Antifungal Thiazole-Carboxamides as SDH Inhibitors

Succinate dehydrogenase inhibitors (SDHIs) are one of the major classes of phytofungicides that inhibit mitochondrial complex II and prevent mitochondrial respiration. Despite their broad applications, only a few SDHIs are available in the market, and rapidly evolving microbes demand the development of new fungicides. In this context, we designed thiazole-carboxamide analogues using structure-guided approaches. The antifungal screening afforded a few potential hits, 22a, with inhibition profiles superior to the comparable Boscalid and Fluxapyroxad across the tested fungi, with substantial selectivity toward Alternaria solani and Pyricularia oryzae. The active compound 22a (S2J-23-04) exhibited significant inhibition of SDH activity (IC₅₀ = 20.01 μM), mycelium inhibition in A. solani (EC₅₀ = 4.49 ± 1.04 μg/mL) and P. oryzae (EC₅₀ = 5.13 ± 1.28 μg/mL), and in vivo activity against A. solani in tomatoes. A slight modification of 22a, i.e., replacing methyl with trifluoromethyl, afforded a superior analogue, 22k (S2J-23-47), with enhanced potency in fungal screening, SDH enzyme, and broad and equipotent mycelium inhibition verified by scanning electron microscopy (SEM). Thus, this study identified a potent selective antifungal lead molecule that can be optimized as a novel phytofungicide.