在4-氨基喹啉侧链中引入分子内氢键基序可增强对耐药恶性疟原虫的活性。
Incorporation of an intramolecular hydrogen-bonding motif in the side chain of 4-aminoquinolines enhances activity against drug-resistant P. falciparum.
作者信息
Madrid Peter B, Liou Ally P, DeRisi Joseph L, Guy R Kiplin
机构信息
Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143-2280, USA.
出版信息
J Med Chem. 2006 Jul 27;49(15):4535-43. doi: 10.1021/jm0600951.
Abstract
Previous data showing that several chloroquine analogues containing an intramolecular hydrogen-bonding motif were potent against multidrug-resistant P. falciparum led to the exploration of the importance of this motif. A series of 116 compounds containing four different alkyl linkers and various aromatic substitutions with hydrogen bond accepting capability was synthesized. The series showed broad potency against the drug-resistant W2 strain of P. falciparum. In particular, a novel series containing variations of the alpha-aminocresol motif gave eight compounds with IC50 values more potent than 5 nM against the W2 strain. Such simple modifications, significantly altering the pKa and sterics of the basic side chain in chloroquine analogues, may prove to be part of a strategy for overcoming the problem of worldwide resistance to affordable antimalarial drugs.
摘要
先前的数据表明，几种含有分子内氢键基序的氯喹类似物对多重耐药恶性疟原虫有效，这促使人们探索该基序的重要性。合成了一系列116种化合物，这些化合物含有四种不同的烷基连接基和具有氢键接受能力的各种芳基取代基。该系列化合物对恶性疟原虫的耐药W2株显示出广泛的效力。特别是，一个含有α-氨基甲酚基序变体的新系列产生了8种化合物，其对W2株的IC50值比5 nM更有效。这种简单的修饰显著改变了氯喹类似物中碱性侧链的pKa和空间结构，可能被证明是克服全球范围内对负担得起的抗疟药物耐药问题策略的一部分。
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本文引用的文献
1
Aminoalkylphenols as antimalarials; simple substituted alpha-aminocresols.作为抗疟药的氨基烷基酚；简单取代的α-氨基甲酚。
J Am Chem Soc. 1946 Oct;68(10):1894-1901. doi: 10.1021/ja01214a008.
2
Aminoalkylphenols as antimalarials (heterocyclicamino)-alpha-amino-o-cresols; the synthesis of camoquin.作为抗疟药的氨基烷基酚（杂环氨基）-α-氨基邻甲酚；卡莫喹的合成
J Am Chem Soc. 1948 Apr;70(4):1363-73. doi: 10.1021/ja01184a023.
3
pfcrt is more than the Plasmodium falciparum chloroquine resistance gene: a functional and evolutionary perspective.疟原虫氯喹抗性转运蛋白（pfcrt）不仅仅是恶性疟原虫的氯喹抗性基因：从功能和进化角度来看
Acta Trop. 2005 Jun;94(3):170-80. doi: 10.1016/j.actatropica.2005.04.004.
4
Effectiveness of antimalarial drugs.抗疟药物的有效性。
N Engl J Med. 2005 Apr 14;352(15):1565-77. doi: 10.1056/NEJMra043207.
5
Synthesis of ring-substituted 4-aminoquinolines and evaluation of their antimalarial activities.环取代4-氨基喹啉的合成及其抗疟活性评价。
Bioorg Med Chem Lett. 2005 Feb 15;15(4):1015-8. doi: 10.1016/j.bmcl.2004.12.037.
6
Transporter of a malaria catastrophe.疟疾灾难的传播者。
Nat Med. 2004 Nov;10(11):1169-71. doi: 10.1038/nm1104-1169.
7
Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents.疟原虫氯喹抗性转运蛋白（PfCRT）在赋予恶性疟原虫对多种抗疟药物耐药性中起核心作用的证据。
Mol Cell. 2004 Sep 24;15(6):867-77. doi: 10.1016/j.molcel.2004.09.012.
8
Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number.恶性疟原虫对甲氟喹的耐药性及 pfmdr1 基因拷贝数增加。
Lancet. 2004;364(9432):438-447. doi: 10.1016/S0140-6736(04)16767-6.
9
The malaria parasite's chloroquine resistance transporter is a member of the drug/metabolite transporter superfamily.疟原虫的氯喹抗性转运蛋白是药物/代谢物转运蛋白超家族的成员。
Mol Biol Evol. 2004 Oct;21(10):1938-49. doi: 10.1093/molbev/msh205. Epub 2004 Jul 7.
10
Parallel synthesis and antimalarial screening of a 4-aminoquinoline library.4-氨基喹啉文库的平行合成与抗疟筛选
J Comb Chem. 2004 May-Jun;6(3):437-42. doi: 10.1021/cc0340473.
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