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

• Published in: Journal of medicinal chemistry Vol. 57; no. 10; pp. 3984 - 3999
• Main Authors: Álvarez, Guzmán, Varela, Javier, Márquez, Pablo, Gabay, Martín, Arias Rivas, Carmen Elena, Cuchilla, Karina, Echeverría, Gustavo A, Piro, Oscar E, Chorilli, Marlus, Leal, Sandra M, Escobar, Patricia, Serna, Elva, Torres, Susana, Yaluff, Gloria, Vera de Bilbao, Ninfa I, González, Mercedes, Cerecetto, Hugo
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.05.2014; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; Drug Stability; Female; Life Sciences & Biomedicine; Mice; Mice, Inbred BALB C; Mutation; Pharmacology & Pharmacy; Science & Technology; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - pharmacology; Trypanocidal Agents - toxicity; Trypanosoma cruzi - drug effects; VITRO; MECHANISM; POTENT 5-NITROFURYL DERIVATIVES; SUSCEPTIBILITY; BIOLOGICAL EVALUATION; INHIBITORS; MICROEMULSION; TRYPANOSOMA-CRUZI STRAINS; BEARING BENZOFUROXAN; BIOAVAILABILITY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm500018m

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.