Madrid Peter B, Liou Ally P, DeRisi Joseph L, Guy R Kiplin
Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143-2280, USA.
J Med Chem. 2006 Jul 27;49(15):4535-43. doi: 10.1021/jm0600951.
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.
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。
