title: (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA]: a purine analogue with trypanocidal activity in vitro and in vivo.
abstract: The unique features of purine salvage systems of pathogenic haemoflagellates render them selectively susceptible to the cytotoxic effects of purine analogues. A series of acyclic nucleoside phosphonates were evaluated for activity against pathogenic haemoflagellates in vitro. One of the phosphonylmethoxyalkylpurines, namely (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], was active in vitro against bloodstream forms of Trypanosoma brucei rhodesiense, T. b. gambiense, multidrug-resistant T. b. brucei, T. congolense and T. evansi, but not against intracellular T. cruzi or Leishmania donovani. Cytotoxic effects against mammalian cells were observed at 4900-27 300-fold higher concentrations than those necessary to inhibit T. b. rhodesiense. (S)-HPMPA was able to eliminate T. b. rhodesiense and multidrug-resistant T. b. brucei in an acute rodent model with two administrations of 10 mg/kg each.
authors.affiliation: Swiss Tropical Institute, Basel, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Kaminsky
authors.forename: C
authors.initials: C
authors.lastname: Schmid
authors.forename: Y
authors.initials: Y
authors.lastname: Grether
authors.forename: A
authors.initials: A
authors.lastname: Holý
authors.forename: E
authors.initials: E
authors.lastname: DeClercq
authors.forename: L
authors.initials: L
authors.lastname: Naesens
authors.forename: R
authors.initials: R
authors.lastname: Brun
mesh_terms: D000208:Acute Disease; D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000627:therapeutic use*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000627:therapeutic use*; D014352:Trypanosomiasis / Q000188:drug therapy* / Q000469:parasitology
chemical_list: D063065:Organophosphonates; D009943:Organophosphorus Compounds; D014344:Trypanocidal Agents; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine