2,4-二氨基喹唑啉类假定二氢叶酸还原酶抑制剂的抗利什曼原虫活性
Antileishmanial activities of 2,4-diaminoquinazoline putative dihydrofolate reductase inhibitors.
作者信息
Berman J D, King M, Edwards N
机构信息
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, D.C. 20307.
出版信息
Antimicrob Agents Chemother. 1989 Nov;33(11):1860-3. doi: 10.1128/AAC.33.11.1860.
Abstract
2,4-Diaminoquinazoline analogs of folate were assessed as antileishmanial agents and as dihydrofolate reductase inhibitors. Against Leishmania major in human macrophages in vitro, two compounds with tertiary amines attached directly to the quinazoline ring were remarkably active. The 50% effective doses were in the picogram per milliliter range (12 to 91 pg/ml), and the in vitro therapeutic indices were approximately 10(5). These compounds were 1,000 times more active on an absolute basis and had a 100 times more favorable therapeutic index than any compound previously tested in this model. Antileishmanial activity was not correlated with activity against Leishmania mexicana promastigote reductase, which suggests that folate utilization in general, rather than reductase activity specifically, was being inhibited.
摘要
叶酸的2,4 - 二氨基喹唑啉类似物被评估为抗利什曼原虫剂和二氢叶酸还原酶抑制剂。在体外人体巨噬细胞中针对硕大利什曼原虫，两种直接连接到喹唑啉环上的叔胺化合物具有显著活性。50%有效剂量在皮克每毫升范围内（12至91 pg/ml），体外治疗指数约为10(5)。这些化合物在绝对基础上活性高1000倍，治疗指数比该模型中先前测试的任何化合物都有利100倍。抗利什曼原虫活性与针对墨西哥利什曼原虫前鞭毛体还原酶的活性不相关，这表明总体上叶酸利用受到抑制，而非特异性还原酶活性受到抑制。
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