Comparative Study of the Inhibition of Metallo-β-Lactamases (IMP-1 and VIM-2) by Thiol Compounds That Contain a Hydrophobic Group(Medicinal Chemistry)

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For the purpose of screening of inhibitors that are effective for wide range of metallo-β-lactamases, the inhibitory effect of two series of compounds, 2-ω-phenylalkyl-3-mercaptopropionic acid (PhenylCnSH (n=1-4)) and N-[(7-chloro-quinoIin-4-ylamino)-alkyl]-3-inercapto-propionamide (QuinolineCnSH n=2-6)), where n denotes the alkyl chain length, on metallo-β-lactamases IMP-1 and VIM-2 was examined. These inhibitors contain a thiol group and a hydrophobic group linked by variable-length methylene chain. PhenylCnSH (n=1-4) was found to be a potent inhibitor of both IMP-1 and VIM-2. PhenylC4SH was the potent inhibitor of both IMP-1 (IC_<50>=1.2μM) and VIM-2 (IC_<50>=1.1μM) among this study. When the number of methylene units was varied, QuinolineC4SH showed the maximum inhibitory activity against IMP-1 and VIM-2 (IC_<50>=2.5μM and IC_<50>=2.4μM). The relationship between the inhibitory effect of the alkyl chain length was different for both series of inhibitors, suggesting that IMP-1 has a tighter binding site than VIM-2. QuinolineCnSH did not serve as a fluorescence reagent for metallo-β-lactamases.
公益社団法人日本薬学会の論文
2004-06-01