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

BACKGROUNDSuccinate 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. RESULTSThe biological assay data showed that compound 3l displayed the most potent antifungal activity with EC50 values of 33.5 and 21.4 mu m against Helminthosporium maydis and Rhizoctonia cerealis, respectively. Moreover, 3l exhibited the best inhibitory ability against SDH enzymes. The results of docking simulation showed that 3l was deeply embedded into the SDH binding pocket, and the binding model was stabilised by a cation- interaction with Arg 43, Tyr 58 and an H-bond with Trp 173. CONCLUSIONThe study suggests that the pyrazole nicotinamide derivative 3l 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. (c) 2016 Society of Chemical Industry