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Design, synthesis and biological evaluation of novel nicotinamide derivatives bearing a substituted pyrazole moiety as potential SDH inhibitors
Author(s) -
Lv XianHai,
Ren ZiLi,
Liu Peng,
Li BingXin,
Li QingShan,
Chu MingJie,
Cao HaiQun
Publication year - 2017
Publication title -
pest management science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.296
H-Index - 125
eISSN - 1526-4998
pISSN - 1526-498X
DOI - 10.1002/ps.4488
Subject(s) - pyrazole , moiety , nicotinamide , lead compound , chemistry , succinate dehydrogenase , docking (animal) , stereochemistry , enzyme , antifungal , biochemistry , combinatorial chemistry , ic50 , in vitro , biology , microbiology and biotechnology , medicine , nursing
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