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.

Development of bis-thiazoles as inhibitors of triosephosphate isomerase from Trypanosoma cruzi. Identification of new non-mutagenic agents that are active in vivo

“…Particularly, the crystal structure of TcTIM in complex with one molecule of (III) was described [12], showing that (III) induces significant changes in the side-chain of Arg71 of loop 3 in one of the monomers of the enzyme. As part of our ongoing program in the search of molecules that could provide drugs for the treatment of Chagas disease, we identified new bioactive furanes bearing thiazole motifs [13,14]. The best examples of these developments were derivatives (IV) and (V) that display excellent in vivo activity without toxic effects such as mutagenicity (Scheme 1).…”

Identification of a New Amide-Containing Thiazole as a Drug Candidate for Treatment of Chagas' Disease

“…Thiazole 4 is in vivo 1.5-to 4.5-fold more active than the parent compound 2 when the parasitemia loads at the maximums are compared (Fig. 5A and B) (10). Additionally, thiazole 4, unlike Bnz and Nfx (see Table S3) (6,28,29), was not mutagenic in the Ames test against the five strains recommended by the OECD, was not genotoxic in vivo at the assayed dose, and possessed a high LD 50 .…”

“…Parasite killing levels caused by the tested compounds were determined as previously described (10)(11)(12).…”

“…For the acute model (10,11), BALB/c male mice (30 days old, 25 to 30 g) bred under specificpathogen-free conditions were infected by intraperitoneal injection with 1 ϫ 10 3 blood trypomastigotes of the Y strain. The mice were divided into three groups.…”

“…For IgG antibody detection (10), all the sera obtained after centrifugation of the blood that were extracted from infected mice were tested twice by enzyme-linked immunosorbent assay (ELISA)…”