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Carbonic anhydrase inhibitors. Characterization and inhibition studies of the most active beta-carbonic anhydrase from Mycobacterium tuberculosis, Rv3588c.

Bioorganic & medicinal chemistry letters (2009-10-23)
Fabrizio Carta, Alfonso Maresca, Adrian Suarez Covarrubias, Sherry L Mowbray, T Alwyn Jones, Claudiu T Supuran
ABSTRACT

The Rv3588c gene product of Mycobacterium tuberculosis, a beta-carbonic anhydrase (CA, EC 4.2.1.1) denominated here mtCA 2, shows the highest catalytic activity for CO(2) hydration (k(cat) of 9.8 x 10(5)s(-1), and k(cat)/K(m) of 9.3 x 10(7)M(-1)s(-1)) among the three beta-CAs encoded in the genome of this pathogen. A series of sulfonamides/sulfamates was assayed for their interaction with mtCA 2, and some diazenylbenzenesulfonamides were synthesized from sulfanilamide/metanilamide by diazotization followed by coupling with amines or phenols. Several low nanomolar mtCA 2 inhibitors have been detected among which acetazolamide, ethoxzolamide and some 4-diazenylbenzenesulfonamides (K(I)s of 9-59 nM). As the Rv3588c gene was shown to be essential to the growth of M. tuberculosis, inhibition of this enzyme may be relevant for the design of antituberculosis drugs possessing a novel mechanism of action.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Sulfanilamide, ≥98%
Sigma-Aldrich
Saccharin, ≥98%
Sigma-Aldrich
p-Toluenesulfonamide, ReagentPlus®, ≥99%
Sigma-Aldrich
Sulfanilamide, puriss. p.a., ≥99% (calc. to the dried substance)
Sigma-Aldrich
Saccharin, ≥99%
Supelco
Sulfanilamide, VETRANAL®, analytical standard
Sigma-Aldrich
4-Sulfamoylbenzoic acid, 97%
Sigma-Aldrich
p-Toluenesulfonamide, reagent grade, 98%
Sigma-Aldrich
(±)-Sulpiride