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

Bioorg Med Chem Lett. 2014 Oct 15;24(20):4891-4. doi: 10.1016/j.bmcl.2014.08.039. Epub 2014 Sep 6.

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.

Keywords: IMP-1; Metallo-β-lactamase; Pseudomonas aeruginosa.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Resistance, Multiple, Bacterial / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Phthalic Acids / chemical synthesis
  • Phthalic Acids / chemistry
  • Phthalic Acids / pharmacology*
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / enzymology
  • Pseudomonas aeruginosa / metabolism
  • Structure-Activity Relationship
  • beta-Lactamases / analysis*
  • beta-Lactamases / chemistry
  • beta-Lactamases / metabolism

Substances

  • 3-(4-hydroxypiperidine-1-yl)phthalic acid
  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Phthalic Acids
  • Piperidines
  • beta-lactamase IMP-1
  • beta-Lactamases