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Abstract:

As a part of our project aimed at the search for new safe chemotherapeutic and chemoprophylactic agents against American trypanosomiasis (Chagas's disease); a series of phosphinopeptides structurally related to glutathione was designed, synthesized, and evaluated as antiproliferative agents against the parasite responsible for this disease, the hemoflagellated protozoan Trypanosoma cruzi. The rationale for the synthesis of these compounds was supported on the basis that the presence of the phosphinic acid moiety would mimic the tetrahedral transition state of trypanothione synthase (TryS), a typical C:N ligase, and the molecular target of these drugs. Of the designed compounds, 53 and 54 were potent growth inhibitors against the clinically more relevant form of T. cruzi (amastigotes) growing in myoblasts. The efficacy for these drugs was comparable to that exhibited by the well-known antiparasitic agent WC-9. The simple phosphinopeptide structure found as a pharmacophore in the present study constitutes a starting point for the development of straightforward optimized drugs. © 2006 American Chemical Society.

Registro:

Documento: Artículo
Título:Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis
Autor:Ravaschino, E.L.; Docampo, R.; Rodriguez, J.B.
Filiación:Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EHA Buenos Aires, Argentina
Center for Global and Emerging Diseases, Department of Cellular Biology, University of Georgia, Athens, GA 30602, United States
Palabras clave:1 butyl [[(gamma glutamylleucyl)amino]methyl]phosphinate; 1 pentyl [[(gamma glutamylleucyl)amino]methyl]phosphinate; phosphinic acid derivative; trypanothione; unclassified drug; amastigote; antiprotozoal activity; article; Chagas disease; drug design; drug efficacy; drug structure; drug synthesis; myoblast; pharmacophore; Trypanosoma cruzi; Amide Synthases; Animals; Antiprotozoal Agents; Cell Proliferation; Drug Design; Glutathione; Molecular Structure; Parasitic Sensitivity Tests; Peptides; Phenyl Ethers; Phosphinic Acids; Spermidine; Structure-Activity Relationship; Thiocyanates; Trypanosoma cruzi
Año:2006
Volumen:49
Número:1
Página de inicio:426
Página de fin:435
DOI: http://dx.doi.org/10.1021/jm050922i
Título revista:Journal of Medicinal Chemistry
Título revista abreviado:J. Med. Chem.
ISSN:00222623
CODEN:JMCMA
CAS:trypanothione, 96304-42-6; 4-phenoxyphenoxyethyl thiocyanate; Amide Synthases, EC 6.3.1.-; Antiprotozoal Agents; Glutathione, 70-18-8; Peptides; Phenyl Ethers; Phosphinic Acids; Spermidine, 124-20-9; Thiocyanates; trypanothione synthetase, EC 6.3.1.9; trypanothione, 96304-42-6
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00222623_v49_n1_p426_Ravaschino

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Citas:

---------- APA ----------
Ravaschino, E.L., Docampo, R. & Rodriguez, J.B. (2006) . Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis. Journal of Medicinal Chemistry, 49(1), 426-435.
http://dx.doi.org/10.1021/jm050922i
---------- CHICAGO ----------
Ravaschino, E.L., Docampo, R., Rodriguez, J.B. "Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis" . Journal of Medicinal Chemistry 49, no. 1 (2006) : 426-435.
http://dx.doi.org/10.1021/jm050922i
---------- MLA ----------
Ravaschino, E.L., Docampo, R., Rodriguez, J.B. "Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis" . Journal of Medicinal Chemistry, vol. 49, no. 1, 2006, pp. 426-435.
http://dx.doi.org/10.1021/jm050922i
---------- VANCOUVER ----------
Ravaschino, E.L., Docampo, R., Rodriguez, J.B. Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis. J. Med. Chem. 2006;49(1):426-435.
http://dx.doi.org/10.1021/jm050922i