3wxc

Publication Abstract from PubMed

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.

X-ray crystallographic analysis of IMP-1 metallo-beta-lactamase complexed with a 3-aminophthalic acid derivative, structure-based drug design, and synthesis of 3,6-disubstituted phthalic acid derivative inhibitors.,Hiraiwa Y, Saito J, Watanabe T, Yamada M, Morinaka A, Fukushima T, Kudo T Bioorg Med Chem Lett. 2014 Oct 15;24(20):4891-4. doi: 10.1016/j.bmcl.2014.08.039., Epub 2014 Sep 6. PMID:25246278^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.