Carbonic anhydrase inhibitors: inhibition of the beta-class enzymes from the fungal pathogens Candida albicans and Cryptococcus neoformans with simple anions

Bioorg Med Chem Lett. 2008 Sep 15;18(18):5066-70. doi: 10.1016/j.bmcl.2008.07.122. Epub 2008 Aug 5.

Abstract

The catalytic activity and inhibition of the beta-carbonic anhydrases (CAs, EC 4.2.1.1) from the pathogenic fungi Candida albicans (Nce103) and Cryptococcus neoformans (Can2) with inorganic anions such as halogenides, pseudohalogenides, bicarbonate, carbonate, nitrate, nitrite, hydrogen sulfide, bisulfite, perchlorate, sulfate were investigated. The two enzymes showed appreciable CO(2) hydrase activity (k(cat) in the range of (3.9-8.0)x10(5)s(-1), and k(cat)/K(m) in the range of (4.3-9.7)x10(7)M(-1)s(-1)). Can2 was weakly inhibited by cyanide and sulfamic acid (K(I)s of 8.22-13.56 mM), while all other anions displayed more potent inhibition. Nce103 was strongly inhibited by cyanide and carbonate (K(I)s of 10-11 microM), and weakly inhibited by sulfate, phenylboronic, and phenyl arsonic acid (K(I)s of 14.15-30.85 mM). These data demonstrate that pathogenic, fungal beta-CAs may be targets for the development of antifungals that have a novel mechanism of action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anions / chemistry
  • Candida albicans / chemistry*
  • Candida albicans / enzymology
  • Carbonates / pharmacology
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase Inhibitors / pharmacology
  • Carbonic Anhydrases / metabolism*
  • Cryptococcus neoformans / chemistry*
  • Cryptococcus neoformans / enzymology
  • Halogens / pharmacology
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Molecular Structure
  • Nitrates / pharmacology
  • Sulfates / pharmacology
  • Sulfides / pharmacology

Substances

  • Anions
  • Carbonates
  • Carbonic Anhydrase Inhibitors
  • Halogens
  • Isoenzymes
  • Nitrates
  • Sulfates
  • Sulfides
  • Carbonic Anhydrases