期刊
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
卷 30, 期 4, 页码 581-585出版社
TAYLOR & FRANCIS LTD
DOI: 10.3109/14756366.2014.956309
关键词
alpha-Carbonic anhydrase; enzyme inhibitor; sulfonamide; Trypanosoma cruzi; quinazoline
资金
- National Plan of Science, Technology and Innovation [11-MED1874-02]
- King Saud University, Riyadh
- 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 Rio de Janeiro (FAPERJ)
The protozoan parasite Trypanosoma cruzi is the agent responsible for trypanosomiasis (Chagas disease) in humans and other animals. It has been recently reported that this pathogen encodes for an alpha-class carbonic anhydrase (CA, EC 4.2.1.1), denominated TcCA, which was shown to be crucial for its life cycle. Inhibition studies of a class of 4-oxoquinazoline containing a benzensulfonamide moiety and their 4-thioxo bioisosteres against the protozoan enzyme TcCA are described here. Most of 4-oxoquinazoline sulfonamides showed nanomolar TcCA inhibition activity with K(I)s in the same order of magnitude of acetazolamide (AAZ), whereas their thioxo bioisosters showed moderate anti-Trypanosoma CA potency with K(I)s in the micromolar range. The discovery of compounds incorporating a 4-oxoquinazoline ring as a low-nanomolar TcCA inhibitor is quite promising and it may be useful for developing anti-Trypanosoma agents with a novel mechanism of action compared to the clinically used drugs (such as benznidazole, nifurtimox) for which significant resistance and serious adverse effects due to their high-toxicity appeared.
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