Inhibition of the β-class carbonic anhydrases from Mycobacterium tuberculosis with carboxylic acids

J Enzyme Inhib Med Chem. 2013 Apr;28(2):392-6. doi: 10.3109/14756366.2011.650168. Epub 2012 Feb 3.

Abstract

The growth of Mycobacterium tuberculosis is strongly inhibited by weak acids although the mechanism by which these compounds act is not completely understood. A series of substituted benzoic acids, nipecotic acid, ortho- and para-coumaric acid, caffeic acid and ferulic acid were investigated as inhibitors of three β-class carbonic anhydrases (CAs, EC 4.2.1.1) from this pathogen, mtCA 1 (Rv1284), mtCA 2 (Rv3588c) and mtCA 3 (Rv3273). All three enzymes were inhibited with efficacies between the submicromolar to the micromolar one, depending on the scaffold present in the carboxylic acid. mtCA 3 was the isoform mostly inhibited by these compounds (K(I)s in the range of 0.11-0.97 µM); followed by mtCA 2 (K(I)s in the range of 0.59-8.10 µM), whereas against mtCA 1, these carboxylic acids showed inhibition constants in the range of 2.25-7.13 µM. This class of relatively underexplored β-CA inhibitors warrant further in vivo studies, as they may have the potential for developing antimycobacterial agents with a diverse mechanism of action compared to the clinically used drugs for which many strains exhibit multi-drug or extensive multi-drug resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biocatalysis
  • Carbon Dioxide / chemistry
  • Carbon Dioxide / metabolism
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism*
  • Carboxylic Acids / chemical synthesis
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Molecular Structure
  • Mycobacterium tuberculosis / enzymology*
  • Mycobacterium tuberculosis / growth & development
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Structure-Activity Relationship

Substances

  • Carbonic Anhydrase Inhibitors
  • Carboxylic Acids
  • Protein Isoforms
  • Carbon Dioxide
  • Carbonic Anhydrases