Guan Jian, Zhang Quan, O'Neil Michael, Obaldia Nicanor, Ager Arba, Gerena Lucia, Lin Ai J
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910, USA.
Antimicrob Agents Chemother. 2005 Dec;49(12):4928-33. doi: 10.1128/AAC.49.12.4928-4933.2005.
WR227825 is an antimalarial pyrroloquinazolinediamine derivative with a high potency but a low therapeutic index. A series of carbamate, carboxamide, succinimide, and alkylamine derivatives of WR227825 were prepared to search for compounds with an improved therapeutic index. The new acetamides and imide showed potent cell growth inhibition against four clones of Plasmodium falciparum (D-6, RCS, W-2, and TM91C235), with a 50% inhibitory concentration of approximately 0.01 ng/ml, and were highly active against Plasmodium berghei, with 100% cure at doses from <0.1 mg/kg of body weight to 220 mg/kg. The carbamates and alkyl derivatives, however, showed weak activity against Plasmodium falciparum cell growth but were highly efficacious in tests against P. berghei by the Thompson test. The best compounds, bis-ethylcarbamate (compound 2a) and tetra-acetamide (3a) derivatives, further demonstrated high potency against the sporozoite Plasmodium yoelii in mice and P. falciparum and Plasmodium vivax in aotus monkeys. Against the AMRU-1 strain of P. vivax, which has four dihydrofolate reductase mutations and is highly resistant to antifolates, tetra-acetamide 3a cured the monkeys at doses of 1 and 3 mg/kg. Compound 2a cured only one out of two monkeys at 3 mg/kg. The results indicated that the new derivatives 2a and 3a not only have retained/improved the antimalarial efficacy of the parent compound WR227825 but also were less toxic to the animals used in the tests.
WR227825是一种抗疟吡咯并喹唑啉二胺衍生物，效力高但治疗指数低。制备了一系列WR227825的氨基甲酸酯、羧酰胺、琥珀酰亚胺和烷基胺衍生物，以寻找治疗指数更高的化合物。新型乙酰胺和酰亚胺对恶性疟原虫的四个克隆株（D-6、RCS、W-2和TM91C235）表现出强大的细胞生长抑制作用，50%抑制浓度约为0.01 ng/ml，对伯氏疟原虫高度活跃，在体重<0.1 mg/kg至220 mg/kg的剂量下治愈率达100%。然而，氨基甲酸酯和烷基衍生物对恶性疟原虫细胞生长的活性较弱，但在汤普森试验中对伯氏疟原虫的测试中疗效显著。最佳化合物双乙基氨基甲酸酯（化合物2a）和四乙酰胺（3a）衍生物，在小鼠体内对约氏疟原虫子孢子以及在夜猴体内对恶性疟原虫和间日疟原虫进一步显示出高效力。对于具有四个二氢叶酸还原酶突变且对抗叶酸药物高度耐药的间日疟原虫AMRU-1株，四乙酰胺3a在1和3 mg/kg的剂量下治愈了猴子。化合物2a在3 mg/kg时仅治愈了两只猴子中的一只。结果表明，新衍生物2a和3a不仅保留/提高了母体化合物WR227825的抗疟疗效，而且对试验所用动物的毒性较小。
