(S)‐9‐(3‐hydroxy‐2‐phosphonylmethoxypropyl)adenine [(S)‐HPMPA]: a purine analogue with trypanocidal activity<i>in vitro</i>and<i>in vivo</i>

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.