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

被引:92
作者
Carta, Fabrizio [1 ]
Maresca, Alfonso [1 ]
Covarrubias, Adrian Suarez [2 ]
Mowbray, Sherry L. [3 ]
Jones, T. Alwyn [2 ]
Supuran, Claudiu T. [1 ]
机构
[1] Univ Florence, Lab Chim Bioinorgan, I-50019 Florence, Italy
[2] Uppsala Univ, Dept Cell & Mol Biol, S-75124 Uppsala, Sweden
[3] Swedish Univ Agr Sci, Dept Mol Biol, SE-75124 Uppsala, Sweden
基金
瑞典研究理事会;
关键词
Carbonic anhydrase; Mycobacterium tuberculosis; Rv3588c; Sulfonamide; Enzyme inhibitor; PATHOGENS CANDIDA-ALBICANS; CRYPTOCOCCUS-NEOFORMANS; HELICOBACTER-PYLORI; SULFAMATE INHIBITORS; GENOME SEQUENCE; CLASS ENZYMES; DNA CLONING; SULFONAMIDES; TARGET; RESISTANCE;
D O I
10.1016/j.bmcl.2009.10.009
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:6649 / 6654
页数:6
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