title: Exploring in vitro and in vivo Hsp90 inhibitors activity against human protozoan parasites.
abstract: 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.
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040, Pomezia, Roma, Italy. Electronic address: giuseppe.giannini@sigma-tau.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040, Pomezia, Roma, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Battistuzzi
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D018512:Parasitemia / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects*; D011485:Protein Binding; D051381:Rats; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*
chemical_list: D000981:Antiprotozoal Agents; D018841:HSP90 Heat-Shock Proteins; D014230:Triazoles
keywords: 1,2,3-Triazole; 3,4-Isoxazolediamide; Heat shock protein inhibitors; Hsp90 inhibitors; Plasmodium falciparum; Trypanosoma brucei rhodesiense