Carbonic anhydrase inhibitors. Inhibition of the β-class enzymes from the fungal pathogens Candida albicans and Cryptococcus neoformans with branched aliphatic/aromatic carboxylates and their derivatives

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2521-6. doi: 10.1016/j.bmcl.2011.02.057. Epub 2011 Feb 17.

Abstract

The inhibition of the β-carbonic anhydrases (CAs, EC 4.2.1.1) from the pathogenic fungi Cryptococcus neoformans (Can2) and Candida albicans (Nce103) with a series of 25 branched aliphatic and aromatic carboxylates has been investigated. Human isoforms hCA I and II were also included in the study for comparison. Aliphatic carboxylates were generally millimolar hCA I and II inhibitors and low micromolar/submicromolar β-CA inhibitors. Aromatic carboxylates were micromolar inhibitors of the four enzymes but some of them showed low nanomolar activity against the fungal pathogenic enzymes. 4-Hydroxy- and 4-methoxy-benzoate inhibited Can2 with K(I)s of 9.5-9.9 nM. The methyl esters, hydroxamates, hydrazides and carboxamides of some of these derivatives were also effective inhibitors of the α- and β-CAs investigated here.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Candida albicans / enzymology*
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase Inhibitors / pharmacology
  • Carbonic Anhydrases / chemistry*
  • Carbonic Anhydrases / metabolism
  • Carboxylic Acids / chemical synthesis
  • Carboxylic Acids / chemistry*
  • Carboxylic Acids / pharmacology
  • Cryptococcus neoformans / enzymology*
  • Fungal Proteins / antagonists & inhibitors*
  • Fungal Proteins / metabolism
  • Humans
  • Structure-Activity Relationship

Substances

  • Carbonic Anhydrase Inhibitors
  • Carboxylic Acids
  • Fungal Proteins
  • Carbonic Anhydrases