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Abstract:

Trypanosomatids possess an unremitting requirement for distinctive endogenous sterols for their life cycle and cannot use the copious availability of cholesterol existing in their mammalian hosts. Exhaustion of endogenous sterols such as ergosterol or of its next biosynthetic product 24-ethylcholesta-5,7,22-trien- 3β-ol brings forth an inhibition of proliferation on Trypanosoma cruzi, the etiologic agent of American trypanosomiasis or Chagas disease. These metabolites are crucial; consequently, the enzymes implicated in catalyzing their formation constitute interesting molecular targets for drug design. Selective inhibition of an enzyme associated to the ergosterol biosynthesis will produce T. cruzi cell arrest. Trypanosomatids, fungi, and yeasts have need of these endogenous sterols for cell viability and growth. In fact, some effective ergosterol biosynthesis inhibitors bearing suitable pharmacokinetic properties in mammals have become putative antiparasitic agents by inducing almost complete parasitological cure in both acute and chronic experimental Chagas disease. WC-9 (compound 7; 4-phenoxyphenoxyethyl thiocyanate) holds our attention bearing in mind that this compound exhibits ED50 values at the low nanomolar range against the clinically more relevant replicative form of T. cruzi (amastigotes). The cellular activity of WC-9 is due to an exhaustion of endogenous sterols demonstrating a blockade of the biosynthetic pathway at a pre-squalene level. © 2016 Bentham Science Publishers.

Registro:

Documento: Artículo
Título:WC-9 a lead drug with great prospects for American trypanosomiasis and toxoplasmosis
Autor:Rodriguez, J.B.
Filiación:Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, Buenos Aires, C1428EHA, Argentina
Palabras clave:Antiparasitic agents; Chagas disease; Squalene synthase; Toxoplasmosis; WC-9; 4 phenoxyphenoxyethyl thiocyanate; ergosterol; squalene synthase; thiocyanic acid derivative; unclassified drug; 4-phenoxyphenoxyethyl thiocyanate; antiparasitic agent; antitrypanosomal agent; diphenyl ether derivative; thiocyanic acid derivative; cell proliferation; Chagas disease; enzyme activity; enzyme inhibition; lipogenesis; nonhuman; Review; structure activity relation; Toxoplasma gondii; toxoplasmosis; Trypanosoma cruzi; animal; Chagas disease; chemistry; drug design; drug effects; human; Toxoplasma; toxoplasmosis; Animals; Antiparasitic Agents; Chagas Disease; Drug Design; Humans; Phenyl Ethers; Thiocyanates; Toxoplasma; Toxoplasmosis; Trypanocidal Agents; Trypanosoma cruzi
Año:2016
Volumen:16
Número:15
Página de inicio:1195
Página de fin:1200
DOI: http://dx.doi.org/10.2174/1389557516666160611015034
Título revista:Mini-Reviews in Medicinal Chemistry
Título revista abreviado:Mini-Rev. Med. Chem.
ISSN:13895575
CODEN:MMCIA
CAS:ergosterol, 23637-22-1, 2418-45-3, 3992-98-1, 57-87-4; squalene synthase, 9077-14-9; 4-phenoxyphenoxyethyl thiocyanate; Antiparasitic Agents; Phenyl Ethers; Thiocyanates; Trypanocidal Agents
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_13895575_v16_n15_p1195_Rodriguez

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Citas:

---------- APA ----------
(2016) . WC-9 a lead drug with great prospects for American trypanosomiasis and toxoplasmosis. Mini-Reviews in Medicinal Chemistry, 16(15), 1195-1200.
http://dx.doi.org/10.2174/1389557516666160611015034
---------- CHICAGO ----------
Rodriguez, J.B. "WC-9 a lead drug with great prospects for American trypanosomiasis and toxoplasmosis" . Mini-Reviews in Medicinal Chemistry 16, no. 15 (2016) : 1195-1200.
http://dx.doi.org/10.2174/1389557516666160611015034
---------- MLA ----------
Rodriguez, J.B. "WC-9 a lead drug with great prospects for American trypanosomiasis and toxoplasmosis" . Mini-Reviews in Medicinal Chemistry, vol. 16, no. 15, 2016, pp. 1195-1200.
http://dx.doi.org/10.2174/1389557516666160611015034
---------- VANCOUVER ----------
Rodriguez, J.B. WC-9 a lead drug with great prospects for American trypanosomiasis and toxoplasmosis. Mini-Rev. Med. Chem. 2016;16(15):1195-1200.
http://dx.doi.org/10.2174/1389557516666160611015034