Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 4, Pages 1761-1771Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm4000616
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Funding
- FP7 EU project (Dynano)
- FP7 EU project (Metoxia)
- Academy of Finland
- Sigrid Juselius Foundation
- Competitive Research Funding of Tampere University Hospital [9N054]
- Coordenacao de Aperfeicoamento Pessoal de Nivel Superior (CAPES)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (MCT/CNPq)
- Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)
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An alpha-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO2 hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K-I values of 192 nM to 84 mu M), whereas some heterocyclic compounds inhibited the enzyme with K-I values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K-I values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo.
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