Design, synthesis and biological evaluation of novel nicotinamide derivatives bearing a substituted pyrazole moiety as potential SDH inhibitors

BACKGROUND Succinate dehydrogenase ( SDH ) plays an important role in the Krebs cycle, which is considered as an attractive target for development of succinate dehydrogenase inhibitors ( SDHIs ) based on antifungal agents. Thus, in order to discover novel molecules with high antifungal activities, SDH as the target for a series of novel nicotinamide derivatives bearing substituted pyrazole moieties were designed and synthesised via a one‐pot reaction. RESULTS The biological assay data showed that compound 3 l displayed the most potent antifungal activity with EC 50 values of 33.5 and 21.4 µ m against Helminthosporium maydis and Rhizoctonia cerealis , respectively. Moreover, 3 l exhibited the best inhibitory ability against SDH enzymes. The results of docking simulation showed that 3 l was deeply embedded into the SDH binding pocket, and the binding model was stabilised by a cation–π interaction with Arg 43, Tyr 58 and an H‐bond with Trp 173. CONCLUSION The study suggests that the pyrazole nicotinamide derivative 3 l may serve as a potential SDHI that can be used as a novel antifungal agent, and provides valuable clues for the further design and optimisation of SDH inhibitors. © 2016 Society of Chemical Industry