Calas M, Cordina G, Bompart J, Ben Bari M, Jei T, Ancelin M L, Vial H
Laboratoire des Aminoacides, Peptides et Proteines, CNRS, UMR 5810, Université de Montpellier II, France.
J Med Chem. 1997 Oct 24;40(22):3557-66. doi: 10.1021/jm9701886.
A series of 80 compounds, primary, secondary, and tertiary amines and quaternary ammonium and bisammonium salts, most of them synthesized as potential choline or ethanolamine analogs, were tested against the in vitro growth of Plasmodium falciparum, the human malaria parasite. They were active over the 10(-3)-10(-8) M concentration range. A structure-activity relationship study was carried out using autocorrelation vectors as structural descriptors, and multidimensional analysis. Principal component analysis, ascending hierarchical classification, and stepwise discriminant analysis showed that both the size and shape of the molecule were essential for antimalarial potency, making the lipophilicity and electronegativity distribution in the molecular space essential. Using the autocorrelogram describing the molecular shape and the electronegativity distribution on the molecular graph, 98% of the molecules were correctly classified either as poorly active or active with only three explanatory variables. The most active compounds were quaternary ammoniums salts whose nitrogen atom had only one long lipophilic chain of 11 or 12 methylene groups (E5, E6, E10, E13, E20, E21, E22, E23, F4, F8), or the bisammoniums whose polar heads were linked by linear alkyl chains of 10 to 12 carbon atoms (G4, G23). The hydroxyethyl group of choline was not very beneficial, whereas the charge and substitutions of nitrogen (aimed at increasing lipophilicity) were essential for optimal interactions. A crude topographic model of the ligand (choline) binding site was thus drawn up.
一系列80种化合物，包括伯胺、仲胺、叔胺以及季铵盐和双铵盐，其中大多数是作为潜在的胆碱或乙醇胺类似物合成的，针对人类疟原虫恶性疟原虫的体外生长进行了测试。它们在10⁻³ - 10⁻⁸ M浓度范围内具有活性。使用自相关向量作为结构描述符进行了构效关系研究，并进行了多维分析。主成分分析、升序层次分类和逐步判别分析表明，分子的大小和形状对于抗疟效力至关重要，这使得分子空间中的亲脂性和电负性分布至关重要。使用描述分子形状和分子图上电负性分布的自相关图，仅用三个解释变量就将98%的分子正确分类为活性低或活性高。活性最高的化合物是季铵盐，其氮原子只有一条由11或12个亚甲基组成的长亲脂链（E5、E6、E10、E13、E20、E21、E22、E23、F4、F8），或者是双铵盐，其极性头由10至12个碳原子的直链烷基连接（G4、G23）。胆碱的羟乙基不是很有益，而氮的电荷和取代（旨在增加亲脂性）对于最佳相互作用至关重要。因此绘制了配体（胆碱）结合位点的粗略拓扑模型。
