Yang Shao-Kang, Kang Joon S, Oelschlaeger Peter, Yang Ke-Wu
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University , Xi'an 710127, P. R. China.
Department of Biological Sciences, California State Polytechnic University , 3801 West Temple Avenue, Pomona, California 91768, United States.
ACS Med Chem Lett. 2015 Feb 12;6(4):455-60. doi: 10.1021/ml500534c. eCollection 2015 Apr 9.
A new scaffold, azolylthioacetamide, was constructed and assayed against metallo-β-lactamases (MβLs). The obtained molecules specifically inhibited MβL ImiS, and 1c was found to be the most potent inhibitor, with a K i = 1.2 μM using imipenem as substrate. Structure-activity relationships reveal that the aromatic carboxyl improves inhibitory activity of the inhibitors, but the aliphatic carboxyl does not. Compounds 1c-d and 1h-i showed the best antibacterial activities against E. coli BL21(DE3) cells producing CcrA or ImiS, resulting in 32- and 8-fold reduction in MIC values, respectively; 1c and 1f-j resulted in a reduction in MIC against P. aeruginosa. Docking studies revealed that 1a, 1c, and 1d fit tightly into the substrate binding site of CphA as a proxy for ImiS with the aromatic carboxylate forming interactions with Lys224, the Zn(II) ion, the backbone of Asn233, and hydrophobic portions of the inhibitors aligning with hydrophobic patches of the protein surface.
构建了一种新的支架唑基硫代乙酰胺，并对金属β-内酰胺酶（MβLs）进行了检测。所得到的分子特异性抑制MβL ImiS，发现1c是最有效的抑制剂，以亚胺培南为底物时其Ki = 1.2 μM。构效关系表明，芳香族羧基可提高抑制剂的抑制活性，而脂肪族羧基则不然。化合物1c - d和1h - i对产生CcrA或ImiS的大肠杆菌BL21(DE3)细胞显示出最佳抗菌活性，MIC值分别降低32倍和8倍；1c和1f - j使铜绿假单胞菌的MIC降低。对接研究表明，1a、1c和1d紧密契合作为ImiS替代物的CphA的底物结合位点，芳香族羧酸盐与Lys224、Zn(II)离子、Asn233的主链形成相互作用，抑制剂的疏水部分与蛋白质表面的疏水区域对齐。
