Azolylthioacetamides as a potent scaffold for the development of metallo-beta-lactamase inhibitors
Azolylthioacetamides as a potent scaffold for the development of metallo-beta-lactamase inhibitors
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唑基硫代乙酰胺作为开发金属-β-内酰胺酶抑制剂的有效支架
DOI：
10.1016/j.bmcl.2017.10.038
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发表时间：
2017
影响因子：
2.7
通讯作者：
Yang Ke Wu
中科院分区：
文献类型：
--
作者：
Yang Xiang;Chang Ya Nan;Ge Ying;Kang Joon S;Zhang Yi Lin;Liu Xiao Long;Oelschlaeger Peter;Yang Ke Wu
为了开发新型金属β-内酰胺酶（MβLs）抑制剂，合成了28种唑基硫代乙酰胺类化合物，并测定了它们的抗MβLs活性。得到的苯并咪唑基和苯并异恶唑基取代基1 - 19特异性抑制酶ImiS，10被发现是ImiS的最有效的抑制剂，IC 50值为15 nM。硝基苯并咪唑取代基20 - 28特异性抑制NDM-1，其中27是最有效的抑制剂，IC 50值为170 nM。对10、11和27的进一步研究揭示了竞争性和非竞争性抑制常数在与IC 50值相似的范围内的混合抑制模式。这些抑制剂导致使用E的亚胺培南MIC值降低2-4倍。大肠杆菌产生ImiS或NDM-1。虽然非竞争性（可能是变构）抑制的来源尚不清楚，但对接研究表明10和11可能与CphA活性部位的Zn 2发生正构相互作用，而27可以通过其硝基桥接NDM-1活性部位的两个Zn（II）离子。
In an effort to develop new inhibitors of metallo-β-lactamases (MβLs), twenty-eight azolylthioacetamides were synthesized and assayed against MβLs. The obtained benzimidazolyl and benzioxazolyl substituted1–19specifically inhibited the enzyme ImiS, and10was found to be the most potent inhibitor of ImiS with an IC50value of 15 nM. The nitrobenzimidazolyl substituted20–28specifically inhibited NDM-1, with27being the most potent inhibitor with an IC50value of 170 nM. Further studies with10,11, and27revealed a mixed inhibition mode with competitive and uncompetitive inhibition constants in a similar range as the IC50values. These inhibitors resulted in a 2–4-fold decrease in imipenem MIC values usingE. colicells producing ImiS or NDM-1. While the source of uncompetitive (possibly allosteric) inhibition remains unclear, docking studies indicate that10and11may interact orthosterically with Zn2 in the active site of CphA, while27could bridge the two Zn(II) ions in the active site of NDM-1viaits nitro group.