title: X-ray crystallographic analysis of IMP-1 metallo-β-lactamase complexed with a 3-aminophthalic acid derivative, structure-based drug design, and synthesis of 3,6-disubstituted phthalic acid derivative inhibitors.
abstract: 3-(4-Hydroxypiperidine-1-yl) phthalic acid 1 shows potent inhibitory activity against metallo-β-lactamase, which is known to inactivate β-lactam antibiotics such as carbapenems. Here, the structure of co-crystals of the metallo-β-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.
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma, Co., Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. Electronic address: yukiko.hiraiwa@meiji.com.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hiraiwa
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma, Co., Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Saito
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma, Co., Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma, Co., Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma, Co., Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Morinaka
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma, Co., Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma, Co., Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kudo
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010795:Phthalic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D013329:Structure-Activity Relationship; D001618:beta-Lactamases / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism
chemical_list: C000596388:3-(4-hydroxypiperidine-1-yl)phthalic acid; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D010795:Phthalic Acids; D010880:Piperidines; C409201:beta-lactamase IMP-1; D001618:beta-Lactamases
keywords: IMP-1; Metallo-β-lactamase; Pseudomonas aeruginosa