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Bioorg Med Chem Lett. 2009 Dec 1;19(23):6649-54. doi: 10.1016/j.bmcl.2009.10.009. Epub 2009 Oct 7.

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

Author information

1
Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, I-50019 Sesto Fiorentino, Firenze, Italy.

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.

PMID:
19846301
DOI:
10.1016/j.bmcl.2009.10.009
[Indexed for MEDLINE]

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