Bioorganic & Medicinal Chemistry Letters 2012-01-01

3-mercapto-1,2,4-triazoles and N-acylated thiosemicarbazides as metallo-β-lactamase inhibitors.

Faridoon, Waleed M Hussein, Peter Vella, Nazar Ul Islam, David L Ollis, Gerhard Schenk, Ross P McGeary

Index: Bioorg. Med. Chem. Lett. 22 , 380-6, (2012)

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Abstract

The production of β-lactamases is an effective strategy by which pathogenic bacteria can develop resistance against β-lactam antibiotics. While inhibitors of serine-β-lactamases are widely used in combination therapy with β-lactam antibiotics, there are no clinically available inhibitors of metallo-β-lactamases (MBLs), and so there is a need for the development of such inhibitors. This work describes the optimisation of a lead inhibitor previously identified by fragment screening of a compound library. We also report that thiosemicarbazide intermediates in the syntheses of these compounds are also moderately potent inhibitors of the IMP-1 MBL from Pseudomonas aeruginosa. The interactions of these inhibitors with the active site of IMP-1 were examined using in silico methods.Copyright © 2011 Elsevier Ltd. All rights reserved.