title: Antitrypanosomal activity of phosphonylmethoxyalkylpurines.
abstract: Phosphonylmethoxyalkylpurines and -pyrimidines exhibit potent activity against a broad spectrum of DNA viruses. We evaluated some of these nucleotide analogues for antitrypanosomal activity in vitro and in mice. The most active compounds were (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl) adenine (HPMPA) and (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)-2,6-diaminopurine (HPMPDAP), which inhibited growth of Trypanosoma brucei brucei by 50% (EC50 value) when incubated in vitro for 24 hr with 0.23-5.69 micrograms drug/ml. Both compounds completely eliminated multidrug-resistant T. b. brucei in culture at 1 microgram/ml after 4-5 days exposure. Mice infected with drug-susceptible T. b. brucei were cured with 2 doses of 10 mg/kg HPMPDAP. Two or 5 doses of 50 mg/kg 9-(2-phosphonylmethoxyethyl) adenine (PMEA) or 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP), respectively, were necessary to eliminate T. b. brucei infections in mice. Mice infected with multidrug-resistant T. b. brucei were not cured with the above dosages. The most active compound against Trypanosoma congolense was PMEDAP with an EC50 value of 3.21-11.63 micrograms/ml. Thus, some of the phosphonylmethoxyalkyl purines showed potential as antitrypanosomal compounds at dosages that are below those toxic for mice.
authors.affiliation: Swiss Tropical Institute, Basel.
authors.forename: R
authors.initials: R
authors.lastname: Kaminsky
authors.forename: E
authors.initials: E
authors.lastname: Zweygarth
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use; D011687:Purines / Q000494:pharmacology* / Q000627:therapeutic use; D014344:Trypanocidal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014348:Trypanosoma congolense / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: C091171:1-(2-phosphonylmethoxyethyl)cytosine; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011687:Purines; D014344:Trypanocidal Agents; C091173:9-(3-hydroxy-2-phosphonomethoxypropyl)-2,6-diaminopurine; C059499:9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine; C053001:adefovir; D003596:Cytosine; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine; D000077404:Cidofovir