Novel Pyrazole-4-acetohydrazide Derivatives Potentially Targeting Fungal Succinate Dehydrogenase: Design, Synthesis, Three-Dimensional Quantitative Structure–Activity Relationship, and Molecular Docking

Abstract

Succinate dehydrogenase inhibitors (SDHIs) have emerged in fungicide markets as one of the fastest-growing categories that are widely applied in agricultural production for crop protection. Currently, the structural modification focusing on the flexible amide link of SDHI molecules is being gradually identified as one of the innovative strategies for developing novel highly efficient and broad-spectrum fungicides. Based on the above structural features, a series of pyrazole-4-acetohydrazide derivatives potentially targeting fungal SDH were constructed and evaluated for their antifungal effects against <i>Rhizoctonia solani</i>, <i>Fusarium graminearum,</i> and <i>Botrytis cinerea</i>. Strikingly, the in vitro EC₅₀ values of constructed pyrazole-4-acetohydrazides <b>6w</b> against <i>R. solani</i>, <b>6c</b> against <i>F. graminearum,</i> and <b>6f</b> against <i>B. cinerea</i> were, respectively, determined as 0.27, 1.94, and 1.93 μg/mL, which were obviously superior to that of boscalid against <i>R. solani</i> (0.94 μg/mL), fluopyram against <i>F. graminearum</i> (9.37 μg/mL), and <i>B. cinerea</i> (1.94 μg/mL). Concurrently, the effects of the substituent steric, electrostatic, hydrophobic, and hydrogen-bond fields on structure-activity relationships were elaborated by the reliable comparative molecular field analysis and comparative molecular similarity index analysis models. Subsequently, the practical value of pyrazole-4-acetohydrazide derivative <b>6w</b> as a potential SDHI was ascertained by the relative surveys on the in vivo anti-<i>R. solani</i> preventative efficacy, inhibitory effects against fungal SDH, and molecular docking studies. The present results provide an indispensable complement for the structural optimization of antifungal leads potentially targeting SDH.