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Bioorg Med Chem. 2016 Mar 1;24(5):1115-20. doi: 10.1016/j.bmc.2016.01.037. Epub 2016 Jan 22.

Sulfonamide inhibition studies of the β-carbonic anhydrase from the pathogenic bacterium Vibrio cholerae.

Author information

1
Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 81, Napoli, Italy; Università degli Studi di Firenze, Dipartimento Di Chimica, Laboratorio di Chimica Bioinorganica, Polo Scientifico, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
2
Università degli Studi di Firenze, Dipartimento Di Chimica, Laboratorio di Chimica Bioinorganica, Polo Scientifico, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
3
Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 81, Napoli, Italy.
4
King Saud University, Department of Chemistry, Riyadh, Saudi Arabia.
5
King Saud University, Department of Chemistry, Riyadh, Saudi Arabia; Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.
6
Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 81, Napoli, Italy. Electronic address: clemente.capasso@ibbr.cnr.it.

Abstract

The genome of the pathogenic bacterium Vibrio cholerae encodes for three carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the α-, β- and γ-classes. VchCA, the α-CA from this species was investigated earlier, whereas the β-class enzyme, VchCAβ was recently cloned, characterized kinetically and its X-ray crystal structure reported by this group. Here we report an inhibition study with sulfonamides and one sulfamate of this enzyme. The best VchCAβ inhibitors were deacetylated acetazolamide and methazolamide and hydrochlorothiazide, which showed inhibition constants of 68.2-87.0nM. Other compounds, with medium potency against VchCAβ, (KIs in the range of 275-463nM), were sulfanilamide, metanilamide, sulthiame and saccharin whereas the clinically used agents such as acetazolamide, methazolamide, ethoxzolamide, dorzolamide, zonisamide and celecoxib were micromolar inhibitors (KIs in the range of 4.51-8.57μM). Identification of potent and possibly selective inhibitors of VchCA and VchCAβ over the human CA isoforms, may lead to pharmacological tools useful for understanding the physiological role(s) of this under-investigated enzymes.

KEYWORDS:

Carbonic anhydrase; Hydratase activity; Inhibitors; Metalloenzymes; Pathogenic bacteria; Sulfonamide

PMID:
26850377
DOI:
10.1016/j.bmc.2016.01.037
[Indexed for MEDLINE]

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