title: Discovery of N-benzoxazol-5-yl-pyrazole-4-carboxamides as nanomolar SQR inhibitors.
abstract: Succinate-ubiquinone oxidoreductase (SQR, EC 1.3.5.1, complex II), an essential component of cellular respiratory chain and tricarboxylic acid (or Krebs) cycle, has been identified as one of the most significant targets for pharmaceutical and agrochemical. Herein, with the aim of discovery of new antibacterial lead structure, a series of N-benzoxazol-5-yl-pyrazole-4-carboxamides were designed, synthesized, and evaluated for their SQR inhibitory effects. Very promisingly, one candidate (Ki = 11 nM, porcine SQR) was successfully identified as the most potent synthetic SQR inhibitor so far. The further inhibitory kinetics studies revealed that the candidate is non-competitive with respect to the substrate cytochrome c and DCIP. Computational simulations revealed that the titled compounds have formed hydrogen bond with D_Y91 and B_W173 and the pyrazole ring formed cation-π interaction with C_R46. In addition, in R(1) position, -CHF2 group has increased the binding affinity and decreased the entropy contribution, while -CF3 group displayed completely opposite effect when bound with SQR. The results of the present work showed that N-benzoxazol-5-yl-pyrazole-4-carboxamide is a new scaffold for discovery of SQR inhibitors and worth further study.
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology, College of Chemistry, Ministry of Education, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Xiong
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology, College of Chemistry, Ministry of Education, Central China Normal University, Wuhan 430079, PR China. Electronic address: xlzhu@mail.ccnu.edu.cn.
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology, College of Chemistry, Ministry of Education, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Shen
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology, College of Chemistry, Ministry of Education, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Wickramabahu Kandergama Wasala Mudiyanselage
authors.initials: WK
authors.lastname: Wishwajith
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology, College of Chemistry, Ministry of Education, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Kui
authors.initials: K
authors.lastname: Li
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology, College of Chemistry, Ministry of Education, Central China Normal University, Wuhan 430079, PR China; Collaborative Innovation Center of Chemical Science and Engineering, Tianjing 30071, PR China. Electronic address: gfyang@mail.ccnu.edu.cn.
authors.forename: Guang-Fu
authors.initials: GF
authors.lastname: Yang
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D055808:Drug Discovery; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D042963:Electron Transport Complex II
keywords: Computational simulations; MM/PBSA; Molecular design; Pyrazole-carboxamides; Succinate–ubiquinone oxidoreductase