Carbonic anhydrase inhibitors: inhibition of the β-class enzyme from the pathogenic yeast Candida glabrata with sulfonamides, sulfamates and sulfamides

Daniela Vullo; Worraanong Leewattanapasuk; Fritz A Mühlschlegel; Antonio Mastrolorenzo; Clemente Capasso; Claudiu T Supuran

doi:10.1016/j.bmcl.2013.02.092

Carbonic anhydrase inhibitors: inhibition of the β-class enzyme from the pathogenic yeast Candida glabrata with sulfonamides, sulfamates and sulfamides

Bioorg Med Chem Lett. 2013 May 1;23(9):2647-52. doi: 10.1016/j.bmcl.2013.02.092. Epub 2013 Mar 1.

Authors

Daniela Vullo¹, Worraanong Leewattanapasuk, Fritz A Mühlschlegel, Antonio Mastrolorenzo, Clemente Capasso, Claudiu T Supuran

Affiliation

¹ Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino, Florence, Italy.

PMID: 23511020
DOI: 10.1016/j.bmcl.2013.02.092

Abstract

The fungal pathogen Candida glabrata encodes for a β-carbonic anhydrase (CA, EC 4.2.1.1), CgNce103, recently discovered. Only anions have been investigated as CgNce103 inhibitors up until now. Here we report the first sulfonamides inhibition study of this enzyme. Simple sulfonamides showed weak or moderate CgNce103 inhibitory properties, whereas acetazolamide, and a series of 4-substituted ureido-benzene-sulfonamides, sulfamates and sulfamides showed effective CgNce103 inhibitory properties, with KIs in the range of 4.1-115 nM, being also ineffective as human CA II inhibitors. As there is significant resistance of C. glabrata clinical isolates to many classical antifungal agents, inhibition of the β-CA from this organism may allow an interesting means of controlling the pathogen growth, eventually leading to antifungals with a novel mechanism of action.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetazolamide / chemistry
Amino Acid Sequence
Antifungal Agents / chemical synthesis
Antifungal Agents / chemistry*
Antifungal Agents / metabolism
Candida glabrata / enzymology*
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry*
Carbonic Anhydrase Inhibitors / metabolism
Carbonic Anhydrases / chemistry*
Carbonic Anhydrases / classification
Carbonic Anhydrases / metabolism
Humans
Kinetics
Molecular Sequence Data
Phylogeny
Protein Binding
Sequence Alignment
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry*
Sulfonamides / metabolism
Sulfonic Acids / chemical synthesis
Sulfonic Acids / chemistry*
Sulfonic Acids / metabolism

Substances

Antifungal Agents
Carbonic Anhydrase Inhibitors
Sulfonamides
Sulfonic Acids
sulfamic acid
Carbonic Anhydrases
Acetazolamide