Triazolylthioacetamide: A Valid Scaffold for the Development of New Delhi Metallo-β-Lactmase-1 (NDM-1) Inhibitors
Triazolylthioacetamide: A Valid Scaffold for the Development of New Delhi Metallo-β-Lactmase-1 (NDM-1) Inhibitors
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三唑基硫代乙酰胺：开发新德里 Metallo-beta-Lactmase-1 (NDM-1) 抑制剂的有效支架
DOI：
10.1021/acsmedchemlett.5b00495
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发表时间：
2016-04-01
影响因子：
4.2
通讯作者：
Yang, Ke-Wu
中科院分区：
文献类型：
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作者：
Zhai, Le;Zhang, Yi-Lin;Yang, Ke-Wu
金属β-内酰胺酶(MβL)裂解β-内酰胺类抗生素的β-内酰胺环，使细菌对这些药物产生耐药性。制备了24个三唑硫代乙酰胺类化合物，并评价了它们作为MβL的三个亚类的代表的抑制剂。化合物4d和6c以头孢唑林为底物，对NDM-1的IC50分别为0.49和0.63mU，对CCRA、IMIS和L1的抑制活性均为部分混合型。构效关系研究表明，氯、杂原子或烷基取代芳环上的氢可以影响生物活性，而保持三唑硫醇的芳环不被修饰则保持抑制效力。对接研究表明，NDM-1的典型有效抑制剂4d和6c在NDM-1的活性部位形成稳定的相互作用，与三唑桥连锌1和锌2，酰胺与赖氨酸211(Lys224)相互作用。
The metallo-beta-lactamases (M beta Ls) cleave the beta-lactam ring of beta-lactam antibiotics, conferring resistance against these drugs to bacteria. Twenty-four triazolylthioacetamides were prepared and evaluated as inhibitors of representatives of the three subclasses of M beta Ls. All these compounds exhibited specific inhibitory activity against NDM-1 with an IC50 value range of 0.15-1.90 mu M, but no activity against CcrA, ImiS, and L1 at inhibitor concentrations of up to 10 mu M. Compounds 4d and 6c are partially mixed inhibitors with K-i values of 0.49 and 0.63 mu M using cefazolin as the substrate. Structure activity relationship studies reveal that replacement of hydrogen on the aromatic ring by chlorine, heteroatoms, or alkyl groups can affect bioactivity, while leaving the aromatic ring of the triazolylthiols unmodified maintains the inhibitory potency. Docking studies reveal that the typical potent inhibitors of NDM-1, 4d and 6c, form stable interactions in the active site of NDM-1, with the triazole bridging Zn1 and Zn2, and the amide interacting with Lys 211 (Lys224).