Synthesis, Biological Evaluation, and 3D-QSAR Studies of <i>N</i>-(Substituted pyridine-4-yl)-1-(substituted phenyl)-5-trifluoromethyl-1<i>H</i>-pyrazole-4-carboxamide Derivatives as Potential Succinate Dehydrogenase Inhibitors

Abstract

A series of new fungicides that can inhibit the succinate dehydrogenase (SDH) was classified and named as SDH inhibitors by the Fungicide Resistance Action Committee in 2009. To develop more potential SDH inhibitors, we designed and synthesized a novel series of <i>N</i>-(substituted pyridine-4-yl)-1-(substituted phenyl)-5-trifluoromethyl-1<i>H</i>-pyrazole-4-carboxamide derivatives, <b>4a</b>-<b>4i</b>, namely, <b>5a</b>-<b>5h</b>, <b>6a</b>-<b>6h</b>, and <b>7a</b>-<b>7j</b>. The bioassay results demonstrated that some title compounds exhibited excellent antifungal activity against four tested phytopathogenic fungi (<i>Gibberella zea</i>, <i>Fusarium oxysporum</i>, <i>Cytospora mandshurica</i>, and <i>Phytophthora infestans</i>). The EC₅₀ values were 1.8 μg/mL for <b>7a</b> against <i>G. zeae</i>, 1.5 and 3.6 μg/mL for <b>7c</b> against <i>F. oxysporum</i> and <i>C. mandshurica</i>, respectively, and 6.8 μg/mL for <b>7f</b> against <i>P. infestans</i>. The SDH enzymatic activity testing revealed that the IC₅₀ values of <b>4c</b>, <b>5f</b>, <b>7f</b>, and penthiopyrad were 12.5, 135.3, 6.9, and 223.9 μg/mL, respectively. The molecular docking results of this series of title compounds with SDH model demonstrated that the compounds could completely locate inside of the pocket, the body fragment formed H bonds, and the phenyl ring showed a π-π interaction with Arg59, suggesting that these novel 5-trifluoromethyl-pyrazole-4-carboxamide derivatives might target SDH. These results could provide a benchmark for understanding the antifungal activity against the phytopathogenic fungus <i>P. infestans</i> and prompt us to discover more potent SDH inhibitors.