Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum
Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum
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DOI：
10.1128/aac.00669-07
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发表时间：
2007-11-01
影响因子：
4.9
通讯作者：
Riscoe, Michael
中科院分区：
文献类型：
--
作者：
Kelly, Jane X.;Smilkstein, Martin J.;Riscoe, Michael
设计、合成了一系列末端含有叔胺基烷基侧链的新型10-N-取代吖啶酮类化合物，并对其增强喹啉类药物抗恶性疟原虫多药耐药性的能力进行了评价。一些吖啶酮类化合物的侧链在环氮和末端氮之间连接了三个或三个以上的碳原子，对恶性疟原虫多药耐药株(DD2)表现出氯喹(CQ)化学增敏活性。等位基因分析表明，在CQ抗性(CQR)寄生菌DD2中，CQ与CQ有显著的协同作用，而在CQ敏感(CQS)D6中，CQ与CQ的交互作用仅为加性(或无差异)。这些吖啶酮衍生物还提高了其他喹啉类抗疟药，如脱乙基氯喹(DCQ)和奎宁(QN)在DD2中的敏感性。与维拉帕米对恶性疟原虫抗Cq转运蛋白(PfCRT)76位氨基酸突变的不同寄生虫株的药敏作用相似。与其他已知的具有精神药物效应的化学增敏剂(如地塞帕明、丙咪嗪和扑尔敏)不同，这些新型吖啶酮衍生物对重要的生物胺类神经递质的摄取或结合没有明显的影响。综合结果表明，10-N-取代吖啶酮类化合物为开发抗恶性疟原虫化学增敏剂提供了新的药效团。
A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for the ability to enhance the potency of quinoline drugs against multidrug-resistant (MDR) Plasmodium falciparum malaria parasites. A number of acridone derivatives, with side chains bridged three or more carbon atoms apart between the ring nitrogen and terminal nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity against the MDR strain of P. falciparum (Dd2). Isobolograrn analysis revealed that selected candidates demonstrated significant synergy with CQ in the CQ-resistant (CQR) parasite Dd2 but only additive (or indifferent) interaction in the CQ-sensitive (CQS) D6. These acridone derivatives also enhanced the sensitivity of other quinoline antimalarials, such as desethylchloroquine (DCQ) and quinine (QN), in Dd2. The patterns of chemosensitizing effects of selected acridones on CQ and QN were similar to those of verapamil against various parasite lines with mutations encoding amino acid 76 of the P. falciparum CQ resistance transporter (PfCRT). Unlike other known chemosensitizers with recognized psychotropic effects (e.g., desipramine, imipramine, and chlorpheniramine), these novel acridone derivatives exhibited no demonstrable effect on the uptake or binding of important biogenic amine neurotransmitters. The combined results indicate that 10-N-substituted acridones present novel pharmacophores for the development of chemosensitizers against P. falciparum.