title: Hydroxamic acid based histone deacetylase inhibitors with confirmed activity against the malaria parasite.
abstract: Recent studies have highlighted a key role in regulating gene transcription, in both eukaryotes and prokaryotes, by enzymes that control the acetylation and deacetylation of histones. In particular, inhibitors of histone deacetylases (HDAC-Is) have been shown effective in controlling the development of many parasites, such as the plasmodium of malaria. Here we report the results of a study aimed at evaluating antiparasitic effect of two classes of HDAC-Is bearing different zinc binding group (hydroxamic acid vs thiol). The study showed that only the hydroxamic acid based HDAC inhibitors were active, with Plasmodium falciparum being the most sensitive parasite, having from low double-digit to single-digit nanomolar range in vitro activities. Among three derivatives evaluated also in vivo, ST8086AA1 (8) effectively inhibited 88% of the development of Plasmodium falciparum.
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
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Roma, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Vignola
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D008288:Malaria / Q000188:drug therapy / Q000662:veterinary; D051379:Mice; D010271:Parasites / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000962:Antimalarials; D004151:Dipeptides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D020033:Protein Isoforms; C000601191:ST8086AA1; D006655:Histone Deacetylases
keywords: Antimalarial activity; Antiprotozoan drug; HDAC inhibitors; Hydroxamic acid; Plasmodium falciparum