Discovery of N-benzoxazol-5-yl-pyrazole-4-carboxamides as nanomolar SQR inhibitors
Discovery of N-benzoxazol-5-yl-pyrazole-4-carboxamides as nanomolar SQR inhibitors
复制标题
发现 N-苯并恶唑-5-基-吡唑-4-甲酰胺作为纳摩尔 SQR 抑制剂
DOI：
10.1016/j.ejmech.2015.03.060
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发表时间：
2015-05-05
影响因子：
6.7
通讯作者：
Yang, Guang-Fu
中科院分区：
文献类型：
--
作者：
Xiong, Li;Zhu, Xiao-Lei;Yang, Guang-Fu
琥珀酸泛醌氧化还原酶（SQR，EC 13.5.1，complex II）是细胞呼吸链和三羧酸（或Krebs）循环的重要组成部分，已被确定为最重要的药物和农药靶标之一。本文以发现新的抗菌先导化合物为目标，设计、合成了一系列N-苯并恶唑-5-基-吡唑-4-甲酰胺类化合物，并对其SQR抑制作用进行了评价。非常有希望的是，一种候选物（Ki = 11 nM，猪SQR）被成功鉴定为迄今为止最有效的合成SQR抑制剂。进一步的抑制动力学研究表明，候选人是非竞争性的底物细胞色素c和DCIP。计算模拟表明，标题化合物与D_Y91和B_W173形成了氢键，吡唑环与C_R46形成了阳离子π相互作用。此外，在R1位，-CHF 2基团增加了结合亲和力，降低了熵贡献，而-CF 3基团与SQR结合时表现出完全相反的效果。结果表明，N-苯并恶唑-5-基-吡唑-4-甲酰胺是一种新的SQR抑制剂骨架，值得进一步研究。(C)2015年Elsevier Masson SAS。All rights reserved.
Succinate-ubiquinone oxidoreductase (SQR, EC 13.5.1, 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 (K-i = 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-pi interaction with C_R46. In addition, in R1 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. (C) 2015 Elsevier Masson SAS. All rights reserved.