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

Summary 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 rbodesiense, 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. rbodesiense. (S)‐HPMPA was able to eliminate T. b. rbodesiense and multidrug‐resistant T. b. brucei in an acute rodent model with two administrations of 10 mg/kg each.