title: Optimization of antitrypanosomatid agents: identification of nonmutagenic drug candidates with in vivo activity.
abstract: Chagas disease, caused by Trypanosoma cruzi parasite, was described thousands of years ago. Currently, it affects millions of people, mostly in Latin America, and there are not suitable drugs for treating it. As an attempt to find appropriate drugs to deal with this problem, we report here on the design, synthesis, and characterization of 82 new compounds. Trypanosomicidal behavior in vitro showed more than 20 outstanding derivatives with anti-Trypanosoma cruzi activity. Furthermore, we studied the nonspecific toxicity against mammalian cells determining their selectivity and also performed mutagenicity studies. Proof of concept, in vivo studies, was conducted with two of the most promising derivatives (77 and 80). They were identified as candidates because they have (i) very simple and cost-effective syntheses; (ii) activity against different stages and strains of the parasite showing excellent in vivo behavior during the acute phase of Chagas disease; and (iii) neither nonspecific toxicity nor mutagenic activity.
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República , 11400 Montevideo, Uruguay.
authors.forename: Guzmán
authors.initials: G
authors.lastname: Álvarez
authors.forename: Javier
authors.initials: J
authors.lastname: Varela
authors.forename: Pablo
authors.initials: P
authors.lastname: Márquez
authors.forename: Martín
authors.initials: M
authors.lastname: Gabay
authors.forename: Carmen Elena
authors.initials: CE
authors.lastname: Arias Rivas
authors.forename: Karina
authors.initials: K
authors.lastname: Cuchilla
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Echeverría
authors.forename: Oscar E
authors.initials: OE
authors.lastname: Piro
authors.forename: Marlus
authors.initials: M
authors.lastname: Chorilli
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Leal
authors.forename: Patricia
authors.initials: P
authors.lastname: Escobar
authors.forename: Elva
authors.initials: E
authors.lastname: Serna
authors.forename: Susana
authors.initials: S
authors.lastname: Torres
authors.forename: Gloria
authors.initials: G
authors.lastname: Yaluff
authors.forename: Ninfa I
authors.initials: NI
authors.lastname: Vera de Bilbao
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
mesh_terms: D000818:Animals; D004355:Drug Stability; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D014344:Trypanocidal Agents