Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-β-lactamase IMP-1

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Arjomandi, Omid Khalili
Hussein, Waleed M
Vella, Peter
Yusof, Yusralina
Sidjabat, Hanna E
Schenk, Gerhard
McGeary, Ross P
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2016
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Abstract

There are currently no clinically available inhibitors of metallo-β-lactamases (MBLs). These enzymes confer resistance to bacteria against a broad range of commonly used β-lactam antibiotics, and are produced by an increasing number of bacterial pathogens. In this study, several thiol derivatives of l-amino acids were designed and synthesized, and their inhibitory effects against the metallo-β-lactamase IMP-1 (subclass B1) were investigated. The most potent compound, derived from l-tyrosine, exhibited competitive inhibition, with a Ki of 86 nM. The ability of this compound to render MBL-expressing bacteria susceptible to imipenem was examined. Reductions in MIC values up to 5.2—fold were observed.

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European Journal of Medicinal Chemistry

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114

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© 2016 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.

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Medicinal and biomolecular chemistry

Organic chemistry

Pharmacology and pharmaceutical sciences

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Arjomandi, OK; Hussein, WM; Vella, P; Yusof, Y; Sidjabat, HE; Schenk, G; McGeary, RP, Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-β-lactamase IMP-1, European Journal of Medicinal Chemistry, 2016, 114, pp. 318-327

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