期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 137, 期 -, 页码 351-364出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.05.061
关键词
Metallo-beta-lactamase; Enzyme inhibition; Antibiotics resistance
资金
- National Health and Medical Research Council [APP1084778]
- University of Queensland
A SAR study on derivatives of 2-amino-1 -benzy1-4,5-diphenyl-1H-pyrrole-3-carbonitrile 5a revealed that the 3-carbonitrile group, vicinal 4,5-diphenyl and N-benzyl side chains of the pyrrole are important for the inhibitory potencies of these compounds against members representing the three main subclasses of metallo-beta-lactamases (MBLs), i.e. IMP-1 (representing the B1 subgroup), CphA (B2) and AIM-1 (B3). Coupling of 5a with a series of acyl chlorides and anhydrides led to the discovery of two N-acylamide derivatives, 10 and 11, as the two most potent IMP-1 inhibitors in this series. However, these compounds are less effective towards CphA and AIM-1. The N-benzoyl derivative of 5a retained potent in vitro activity against each of MBLs tested (with inhibition constants in the low mu M range). Importantly, this compound also significantly enhanced the sensitivity of IMP-1, CphA- or AIM-1-producing cell cultures towards meropenem. This compound presents a promising starting point for the development of a universal MBL inhibitor, targeting members of each of the major subgroups of this family of enzymes. (C) 2017 Elsevier Masson SAS. All rights reserved.
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