Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 19, Issue 23, Pages 6649-6654Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2009.10.009
Keywords
Carbonic anhydrase; Mycobacterium tuberculosis; Rv3588c; Sulfonamide; Enzyme inhibitor
Categories
Funding
- Sixth Framework Programme of the European Union
- Foundation for Strategic Research
- Swedish Research Council
- EU [NM4TB CT: 018923]
- Uppsala University
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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 CO2 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. (C) 2009 Elsevier Ltd. All rights reserved.
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