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, <b>22a</b>, with inhibition profiles superior to the comparable Boscalid and Fluxapyroxad across the tested fungi, with substantial selectivity toward <i>Alternaria solani</i> and <i>Pyricularia oryzae</i>. The active compound <b>22a</b> (S2J-23-04) exhibited significant inhibition of SDH activity (IC₅₀ = 20.01 μM), mycelium inhibition in <i>A. solani</i> (EC₅₀ = 4.49 ± 1.04 μg/mL) and <i>P. oryzae</i> (EC₅₀ = 5.13 ± 1.28 μg/mL), and <i>in vivo</i> activity against <i>A. solani</i> in tomatoes. A slight modification of <b>22a</b>, <i>i.e.</i>, replacing methyl with trifluoromethyl, afforded a superior analogue, <b>22k</b> (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.