Structure-activity relationships in 4-aminoquinoline antiplasmodials. The role of the group at the 7-position
Structure-activity relationships in 4-aminoquinoline antiplasmodials. The role of the group at the 7-position
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DOI：
10.1021/jm020858u
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发表时间：
2002-08-01
影响因子：
7.3
通讯作者：
Monti, D
中科院分区：
文献类型：
--
作者：
Kaschula, CH;Egan, TJ;Monti, D
本文研究了喹啉环7位上有11个不同取代基的N-1，N-1-二乙基-N-2-（4-喹啉基）-1，2-乙二胺类化合物对氯喹敏感的恶性疟原虫D10株的体外抗疟活性。已显示在7位的吸电子基团降低喹啉环氮原子和烷基侧链中叔氨基氮的pK（a）。喹啉氮的pKa（a）范围为硝基衍生物中的6.28至氨基衍生物中的8.36，而叔氨基氮的pKa范围为三氟甲基衍生物中的7.65至氨基衍生物中的10.02。计算表明，这些化合物在寄生虫食物泡中的pH捕获范围在氯喹中观察到的NO2衍生物的约7%和氨基衍生物的97%之间。观察到针对pH捕获标准化的抗疟原虫活性与β-正铁血红素抑制活性之间成正比。活动不能与任何其他观察到的物理参数。这些衍生物的β-血红素抑制活性似乎与血红素-喹啉缔合常数和7位基团的吸电子能力（Hammett常数）相关。对于所研究的化合物，血红素缔合常数反过来又受到7位基团亲脂性的影响。
Antiplasmodial activities versus the chloroquine sensitive D10 strain of Plasmodium falciparum of a series of N-1,N-1-diethyl-N-2-(4-quinolinyl)-1,2-ethanediamines with 11 different substituents at the 7-position on the quinoline ring have been investigated in vitro. Electron-withdrawing groups at the 7-position have been shown to lower the pK(a) of both the quinoline ring nitrogen atom and the tertiary amino nitrogen in the alkyl side chain. The quinoline nitrogen pK(a) ranges from 6.28 in the nitro derivative to 8.36 in the amino derivative, while the tertiary amino nitrogen has a pKa ranging between 7.65 in the trifluoromethyl derivative and 10.02 in the amino derivative. Calculation suggests that the resulting pH trapping of these compounds in the parasite food vacuole ranges between about 7% of that observed in chloroquine for the NO2 derivative and 97% in the amino derivative. A direct proportionality between antiplasmodial activity normalized for pH trapping and beta-hematin inhibitory activity was observed. Activity could not be correlated with any other observed physical parameter. The beta-hematin inhibitory activity of these derivatives appears to correlate with both the hematin-quinoline association constant and the electron-withdrawing capacity of the group at the 7-position (Hammett constant). For the compounds under investigation, the hematin association constant is in turn influenced by the lipophilicity of the group at the 7-position.