CRYSTAL AND MOLECULAR-STRUCTURE OF THE ANTIMALARIAL AGENT ENPIROLINE
CRYSTAL AND MOLECULAR-STRUCTURE OF THE ANTIMALARIAL AGENT ENPIROLINE
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DOI：
10.1128/aac.33.7.1081
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发表时间：
1989-07-01
影响因子：
4.9
通讯作者：
KARLE, IL
中科院分区：
文献类型：
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作者：
KARLE, JM;KARLE, IL
为了确定氨基醇类抗疟药的共同空间和结构特征，最终设计出更有效的药物，并更好地了解这类抗疟药的作用机制，研究具有抗氯喹耐药性恶性疟原虫活性的新型抗疟药enpiroline的三维晶体和分子结构，用x射线晶体学测定了金鸡纳生物碱的晶体结构，并与新型抗疟药WR 194,965进行了比较。苯基吡啶环体系的芳香环相互扭曲约18度。enpioline分子内脂肪族N-O距离为2.80 . ang。(1 .ANG。= 0.1 nm)，与抗疟金鸡纳生物碱的N-O距离接近。enpioline既包含脂肪族氮和氧原子之间的分子内氢键，也包含两个相邻分子中脂肪族氮和氧原子之间的分子间氢键。其中一种对映体与奎宁的叠加效果最好，另一种对映体与奎尼丁的叠加效果最好，这表明两种对映体都具有抗疟疾活性。由于氨基酸醇类抗疟药晶体结构的一个共同特征是分子间氢键的形成，氢键形成的共同空间方向表明这些抗疟药与共同受体位点结合的潜在能力。晶体学参数为：c19h18f6n50o；Mr = 404.3；单位胞对称，单斜；空间组，P21/a；单元参数cell.sbd.a = 9.454 .+-。0.004 .ANG。， b = 18.908 .+-。0.008 .ANG。， c = 10.300 .+-。0.004 .ANG。，和。beta。= 96.55 .+-。0.03%;V（单胞体积）= 1829.2 .ANG.3；Z（单位细胞分子数）= 4；Dx（计算密度）= 1.46 g cm-3；辐射源cuk。(.lambda。= 1.54178 . ang .)；.mu。（吸收系数）= 11.49 cm-1；F(000)（零散射角原子散射因子之和）= 832；房间温度;1798次反射的最终R = 8.7%
To identify common spatial and structural features of amino alcohol antimalarial agents with the eventual goal of designing more effective drugs and a better understanding of the mechanism of action of this class of antimalarial agents, the three-dimensional crystal and molecular structure of enpiroline, a new antimalarial agent active against chloroquine-resistant Plasmodium falciparum, was determined by X-ray crystallography and compared with the crystal structures of the cinchona alkaloids and of the new antimalarial agent WR 194,965. The aromatic rings of the phenyl-pyridine ring system of enpiroline are twisted from each other by approximately 18.degree.. The intramolecular aliphatic N-O distance in enpiroline was 2.80 .ANG. (1 .ANG. = 0.1 nm), which is close to the N-O distance found in the antimalarial cinchona alkaloids. Enpiroline contains both an intramolecular hydrogen bond between the aliphatic nitrogen and oxygen atoms and an intermolecular hydrogen bond between the aliphatic nitrogen and oxygen atoms of two neighboring molecules. One enantiomer of enpiroline superimposed best with quinine, and the other enantiomer of enpiroline superimposed best with quinidine, suggesting that both enantiomers of enpiroline possess antimalarial activity. Since a common feature of the crystal structures of the amino acid alcohol antimalarial agents is the formation of intermolecular hydrogen bonds, the common spatial direction of hydrogen bond formation indicates the potential ability of these antimalarial agents to bind to a common receptor site. The crystallographic parameters were as follows: C19H18F6N5O; Mr = 404.3; symmetry of unit cell, monoclinic; space group, P21/a; parameters of unit cell.sbd.a = 9.454 .+-. 0.004 .ANG., b = 18.908 .+-. 0.008 .ANG., c = 10.300 .+-. 0.004 .ANG., and .beta. = 96.55 .+-. 0.03%; V (volume of unit cell) = 1829.2 .ANG.3; Z (number of molecules per unit cell) = 4; Dx (calculated density) = 1.46 g cm-3; source of radiation, CuK.alpha. (.lambda. = 1.54178 .ANG.); .mu. (absorption coefficient) = 11.49 cm-1; F(000) (sum of atomic scattering factors at zero scattering angle) = 832; room temperature; final R = 8.7% for 1,798 reflections with