Incorporation of an intramolecular hydrogen-bonding motif in the side chain of 4-aminoquinolines enhances activity against drug-resistant P-falciparum
Incorporation of an intramolecular hydrogen-bonding motif in the side chain of 4-aminoquinolines enhances activity against drug-resistant P-falciparum
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DOI：
10.1021/jm0600951
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发表时间：
2006-07-27
影响因子：
7.3
通讯作者：
Guy, R. Kiplin
中科院分区：
文献类型：
--
作者：
Madrid, Peter B.;Liou, Ally P.;Guy, R. Kiplin
先前的数据显示，几种含有分子内氢键基序的氯喹类似物对耐多药恶性疟原虫具有很强的抗药性，这导致了对这一基序重要性的探索。合成了一系列116个具有氢键接受能力的化合物，其中包括4种不同的烷基连接物和各种芳香族取代基。该系列对耐药的恶性疟原虫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化合物给出了8个IC50值超过5 nM的化合物对W2菌株的抑制作用。这种简单的修改，显著改变氯喹类似物中碱性侧链的pK(A)和立体结构，可能被证明是克服世界范围内对负担得起的抗疟疾药物抗药性问题的战略的一部分。
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 pK(a) 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.