Optimization of Antitrypanosomatid Agents: Identification of Nonmutagenic Drug Candidates with in Vivo Activity


Autoria(s): Alvarez, Guzman; Varela, Javier; Marquez, Pablo; Gabay, Martin; Arias Rivas, Carmen Elena; Cuchilla, Karina; Echeverria, Gustavo A.; Piro, Oscar E.; Chorilli, Marlus; Leal, Sandra M.; Escobar, Patricia; Serna, Elva; Torres, Susana; Yaluff, Gloria; Vera de Bilbao, Ninfa I.; Gonzalez, Mercedes; Cerecetto, Hugo
Contribuinte(s)

Universidade Estadual Paulista (UNESP)

Data(s)

03/12/2014

03/12/2014

22/05/2014

Resumo

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

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.

Formato

3984-3999

Identificador

http://dx.doi.org/10.1021/jm500018m

Journal Of Medicinal Chemistry. Washington: Amer Chemical Soc, v. 57, n. 10, p. 3984-3999, 2014.

0022-2623

http://hdl.handle.net/11449/113468

10.1021/jm500018m

WOS:000336510100006

Idioma(s)

eng

Publicador

Amer Chemical Soc

Relação

Journal of Medicinal Chemistry

Direitos

closedAccess

Tipo

info:eu-repo/semantics/article