title: Identification of a new amide-containing thiazole as a drug candidate for treatment of Chagas' disease.
abstract: Although the parasitic infection Chagas' disease was described over 100 years ago, even now there are not suitable drugs. The available drugs nifurtimox and benznidazole have limited efficacies and tolerances, with proven mutagenic effects. Attempting to find appropriate drugs to deal with this problem, here we report on the development and pharmacological characterization of new amide-containing thiazoles. In the present study, we evaluated the in vitro and in vivo effects of new candidates against Trypanosoma cruzi, the etiological agent of Chagas' disease. The lead amide-containing thiazole derivative had potent in vitro activity, an absence of both in vitro mutagenic and in vivo clastogenic effects, and excellent in vitro selectivity and in vivo tolerance. The compound suppressed parasitemia in mice, modifying the anti-T. cruzi antibodies like the reference drug, benznidazole, and displayed the lowest mortality among the tested drugs. The present evidence suggests that this compound is a promising anti-T. cruzi agent surpassing the lead optimization stage in drug development and leading to a candidate for preclinical study.
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
authors.forename: Guzmán
authors.initials: G
authors.lastname: Álvarez
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
authors.forename: Javier
authors.initials: J
authors.lastname: Varela
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Cruces
authors.affiliation: Laboratorio de Experimentación Animal, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Fernández
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
authors.forename: Martín
authors.initials: M
authors.lastname: Gabay
authors.affiliation: Centro de Investigaciones de Enfermedades Tropicales, Departamento de Ciencias Básicas, Universidad Industrial de Santander, Bucaramanga, Colombia.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Leal
authors.affiliation: Centro de Investigaciones de Enfermedades Tropicales, Departamento de Ciencias Básicas, Universidad Industrial de Santander, Bucaramanga, Colombia.
authors.forename: Patricia
authors.initials: P
authors.lastname: Escobar
authors.affiliation: Departamento de Medicina Tropical, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, Asunción, Paraguay.
authors.forename: Luis
authors.initials: L
authors.lastname: Sanabria
authors.affiliation: Departamento de Medicina Tropical, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, Asunción, Paraguay.
authors.forename: Elva
authors.initials: E
authors.lastname: Serna
authors.affiliation: Departamento de Medicina Tropical, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, Asunción, Paraguay.
authors.forename: Susana
authors.initials: S
authors.lastname: Torres
authors.affiliation: Departamento de Anatomía Patológica, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, Asunción, Paraguay.
authors.forename: Susy J
authors.initials: SJ
authors.lastname: Figueredo Thiel
authors.affiliation: Departamento de Medicina Tropical, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, Asunción, Paraguay.
authors.forename: Gloria
authors.initials: G
authors.lastname: Yaluff
authors.affiliation: Departamento de Medicina Tropical, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, Asunción, Paraguay.
authors.forename: Ninfa I
authors.initials: NI
authors.lastname: Vera de Bilbao
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay hcerecetto@cin.edu.uy megonzal@fq.edu.uy.
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay hcerecetto@cin.edu.uy megonzal@fq.edu.uy.
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000473:pathology; D055808:Drug Discovery; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000254:growth & development
chemical_list: D000577:Amides; D013844:Thiazoles; D014344:Trypanocidal Agents