Molecular electronic properties of a series of 4-quinolinecarbinolamines define antimalarial activity profile
Molecular electronic properties of a series of 4-quinolinecarbinolamines define antimalarial activity profile
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DOI：
10.1021/jm960358z
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发表时间：
1996-11-08
影响因子：
7.3
通讯作者：
Karle, JM
中科院分区：
文献类型：
--
作者：
Bhattacharjee, AK;Karle, JM
使用半经验奥斯汀模型 1 (AM1) 量子化学方法对一系列 4-喹啉甲醇胺抗疟药进行了详细的计算研究，将电子特征与抗疟活性相关联，并更全面地阐明影响化合物功能和效用的基本分子水平力。对本系列中的先导化合物甲氟喹进行从头算（3-21G 级）计算，以检查 AM1 方法的可靠性。分子特定区域的电子密度似乎对活性起着关键作用。喹啉环氮原子正面部分的大横向延伸负电位和分子平面上不存在负电位对于有效的抗疟药至关重要。这些静电特征可能是化合物疏水性或亲脂性的调节剂，因此决定了它们的活性。羟基氢原子所具有的正电位的大小也与有效的抗疟活性相关。两个负电位区域出现在羟基氧和哌啶基氮原子附近。两个负电势区域和羟基氢原子所在的正电势与细胞效应物的分子间氢键作用一致。目前的建模研究应有助于有效设计此类抗疟药物。
A detailed computational study on a series of 4-quinolinecarbinolamine antimalarials was performed using the semiempirical Austin model 1 (AM1) quantum chemical method to correlate the electronic features with antimalarial activity and to illuminate more completely the fundamental molecular level forces that affect the function and utility of the compounds. Ab initio (3-21G level) calculations were performed on mefloquine, the lead compound in this series, to check the reliability of the AM1 method. Electron density in specific regions of the molecules appears to play the pivotal role toward activity. A large laterally extended negative potential in the frontal portion of the nitrogen atom of the quinoline ring and the absence of negative potential over the molecular plane are crucial for the potent antimalarials, These electrostatic features are likely to be the modulator of hydrophobicity or lipophilicity of the compounds and, hence, determine their activities. The magnitude of the positive potential located by the hydroxyl hydrogen atom also correlates with potent antimalarial activity. Two negative potential regions occur near the hydroxyl oxygen and piperidyl nitrogen atoms. The two negative potential regions and the positive potential located by the hydroxyl hydrogen atom are consistent with intermolecular hydrogen bonding with the cellular effecters. The present modeling study should aid in efficient designing of this class of antimalarial agents.