期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 24, 期 20, 页码 4891-4894出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2014.08.039
关键词
Metallo-beta-lactamase; IMP-1; Pseudomonas aeruginosa
3-(4-Hydroxypiperidine-1-yl) phthalic acid 1 shows potent inhibitory activity against metallo-beta-lactamase, which is known to inactivate beta-lactam antibiotics such as carbapenems. Here, the structure of co-crystals of the metallo-beta-lactamase IMP-1 and 1 was first analyzed by X-ray crystallography, and then used for structure-based drug design. Four novel compounds bearing substituents at the 6-position were synthesized to produce 3,6-disubstituted phthalic acid derivatives, and their IMP-1 inhibitory activity and synergistic effect with the carbapenem biapenem (BIPM) were evaluated. 3,6-Disubstituted phthalic acid derivatives showed potent IMP-1 inhibitory activity. In particular, compound 13 showed 10-fold higher IMP-1 inhibitory activity as compared with the parent derivative 1. (C) 2014 Elsevier Ltd. All rights reserved.
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