Exploring in vitro and in vivo Hsp90 inhibitors activity against human protozoan parasites
- Bioorg Med Chem Lett. 2015 Feb 1;25(3):462-5. doi: 10.1016/j.bmcl.2014.12.048.
- 1. R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040, Pomezia, Roma, Italy. Electronic address: [email protected].
- 2. R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040, Pomezia, Roma, Italy.
A set of compounds, previously selected as potent Hsp90α inhibitors, has been studied on a panel of human parasites. 5-Aryl-3,4-isoxazolediamide derivatives (1) were active against two protozoa, Trypanosoma brucei rhodesiense and Plasmodium falciparum, with a good tolerability toward cytotoxicity on non-malignant L6 rat myoblast cell line, unlike the 1,5-diaryl,4-carboxamides-1,2,3-triazole derivatives (2) which, while showing a single-digit nM range activity against the same protozoa, were also highly cytotoxic on L6 cells. In a subsequent in vivo study, two isoxazolediamide derivatives, 1a and 1b, were very efficacious on the sleeping sickness-causing agent with a clear parasitaemia during treatment. These data, however, showed that not all protozoa are sensitive to HSP90 inhibitors, as well as not all HSP90 inhibitors are equally active on parasites.