Structure−Activity Relationship of New Growth Inhibitors of Trypanosoma cruzi

Abstract

Several drugs bearing the 4-phenoxyphenoxy skeleton and other closely related structures were designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the etiologic agent of Chagas' disease. The new class of drugs was envisioned by modifying the nonpolar 4-phenoxyphenoxy moiety replacing selected aromatic protons by different groups via electrophilic aromatic substitution reactions as well as introducing a sulfur atom at the polar extreme. Of the designed compounds, sulfur-containing derivatives were shown to be potent antireplicative agents against T. cruzi. Among these drugs, 4-phenoxyphenoxyethyl thiocyanate (compound 56) proved to be an extremely active growth inhibitor of the epimastigote forms of T. cruzi and displayed an IC50 of 2.2 microM. Under the same assay conditions, this drug was much more active than Nifurtimox, one of the drugs currently in clinical use to control this disease. This thiocyanate derivative was also a very active inhibitor against the intracellular form of the parasite at the nanomolar level. Other sulfur derivatives prepared also exhibited very potent antiproliferative action against T. cruzi. The presence of a sulfur atom at the polar extreme for this family of compounds seems to be very important for biological action because this atom was always associated with high inhibition values. 4-Phenoxyphenoxyethyl thiocyanate presents very good prospective not only as a lead drug but also as a potential chemotherapeutic agent.

Microsatellite and Mini-Exon Analysis of Mexican Human DTU ITrypanosoma cruziStrains and Their Susceptibility to Nifurtimox and Benznidazole

“…Only the Mexican strain H1 was resistant to both drugs, according to the criteria established in previous studies, because it had IC 50 G and IC 50 M values higher than 50 lM (Nirdé et al 1995, Villarreal et al 2005. The IC 50 M and IC 50 G values for the other Mexican strains were heterogeneous, and they were comparable with values reported for South American strains, such as Tulahuen 2 (TcIV), Dm28c (TcI), Silvio (TcI), Esmeraldo (TcII), and Y (TcII) (Cinque et al 1998, Vieites et al 2008, Wilkinson et al 2008, Luna et al 2009.…”

A Critical Review on Chagas Disease Chemotherapy

“…Fenoxycarb and analogs were synthesized, and assays with epimastigotes suggested that an allyl ether moiety bonded at the polar extreme is important for the trypanocidal effect (Cinque et al 1998). Some analogs were also active against bloodstream forms and reduced the parasitemia and mortality levels in relation to untreated controls (Fichera et al 1995).…”

Update on Chagas' disease in Mexico

“…9 Their efficacy is also limited to the acute phase of the infection, and it is highly variable so that there is still controversial evidence that patients really benefit from such treatments. 10 A variety of new drugs is thus currently under development, [20][21][22][23][24] and some appear to show promise. However, additional studies are necessary and it will be some time before new treatments become available.…”