期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 52, 期 8, 页码 2226-2232出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm9000488
关键词
-
资金
- 6th Framework Programme
- European Union (DeZnIT project)
The beta-carbonic anhydrase (CA, EC 4.2. 1.1) encoded by the gene Rv 1284 (mtCA 1) of Mycobacterium tuberculosis shows appreciable catalytic activity for CO, hydration, with a k(cat) of 3.9 x 10(5) s(-1) and a k(cat)/K-m of 3.7 x 10(7) M-1 s(-1). A panel of 36 sulfonamides and one sulfamate, some of which are used clinically, were assayed for their effect on mtCA 1 catalytic activity. Most sulfonamides exhibited K-1 values in the range of 1-10 mu M, but several derivatives, including sulfanilyl-sulfonamides acetazolamide, methazolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide, and the sulfamate topiramate, exhibited submicromolar inhibition (K-I values of 0.481-0.905 mu M). The best inhibitors were 3-bromosulfanilamide and indisulam (K-1 values of 97-186 nM). This study demonstrates that mtCA 1 can be inhibited by sulfonarnides and sulfamates and thus has potential for developing antimycobacterial agents with an alternate mechanism of action. This is an important finding to explore further, as many strains exhibit multidrug resistance and extensive multidrug resistance to existing therapeutics.
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