Kaminsky R, Zweygarth E, De Clercq E
Swiss Tropical Institute, Basel.
J Parasitol. 1994 Dec;80(6):1026-30.
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.
膦酰甲氧基烷基嘌呤和嘧啶对多种DNA病毒具有强大的活性。我们评估了其中一些核苷酸类似物在体外和小鼠体内的抗锥虫活性。最具活性的化合物是（S）-9-（3-羟基-2-膦酰甲氧基丙基）腺嘌呤（HPMPA）和（S）-9-（3-羟基-2-膦酰甲氧基丙基）-2,6-二氨基嘌呤（HPMPDAP），当在体外与0.23 - 5.69微克药物/毫升孵育24小时时，它们可使布氏布氏锥虫的生长抑制50%（EC50值）。两种化合物在1微克/毫升浓度下暴露4 - 5天后，可完全消除培养物中的多药耐药布氏布氏锥虫。感染药物敏感布氏布氏锥虫的小鼠用两剂10毫克/千克的HPMPDAP治愈。分别需要两剂或五剂50毫克/千克的9-（2-膦酰甲氧基乙基）腺嘌呤（PMEA）或9-（2-膦酰甲氧基乙基）-2,6-二氨基嘌呤（PMEDAP）才能消除小鼠体内的布氏布氏锥虫感染。感染多药耐药布氏布氏锥虫的小鼠用上述剂量无法治愈。对刚果锥虫最具活性的化合物是PMEDAP，其EC50值为3.21 - 11.63微克/毫升。因此，一些膦酰甲氧基烷基嘌呤在低于对小鼠有毒的剂量下显示出作为抗锥虫化合物的潜力。
