Design, synthesis, crystal structure, fungicidal activity and in silico study of novel pyrazole carboxamide derivatives containing flexible chain

Abstract

Pyrazole-containing compounds are significant in agrochemical discovery due to their diverse biological activities. Inspired by commercial succinate dehydrogenase inhibitor (SDHI) fungicides featuring flexible linkers, a series of novel pyrazole-carboxamide derivatives containing a flexible chain were designed and synthesized to explore new fungicidal agents. Fifteen target compounds (6a–6o) were successfully synthesized and characterized. In vitro fungicidal evaluation against ten plant pathogens at 50 µg/mL revealed that most compounds exhibited selective and moderate activity. Compound 6b demonstrated notable efficacy against Sclerotinia sclerotiorum (87.5% inhibition). X-ray crystallography of 6b confirmed its molecular structure and revealed intermolecular interactions stabilized by hydrogen bonding and π-stacking. Hirshfeld surface, energy framework, and DFT analyses provided insights into crystal packing and electronic properties. Molecular docking and MD simulation indicated that 6b binds to SDH via multiple hydrogen bonds and π-interactions, with a binding affinity comparable to that of the commercial SDHI fluopyram. A novel class of flexible-chain-containing pyrazole-carboxamide derivatives was developed, with compound 6b identified as a promising lead structure for further optimization. The integrated synthetic, bioassay, crystallographic, and computational studies establish a foundation for structure–activity relationship analysis and future design of new fungicidal candidates.