Joubert Jacques, Fortuin Elton E, Taylor Dale, Smith Peter J, Malan Sarel F
School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa.
School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa.
Bioorg Med Chem Lett. 2014 Dec 1;24(23):5516-9. doi: 10.1016/j.bmcl.2014.09.088. Epub 2014 Oct 6.
The control of malaria has been complicated by increased resistance of the malaria parasite to existing antimalarials such as chloroquine (CQ). Herein, we report the ability of NGP1-01, the prototype pentacycloundecylamine (PCU), to reverse CQ resistance (>50%) and act as a chemosensitizer. Based on this finding we set out to synthesize a small series of novel agents comprising of a PCU moiety as the reversal agent conjugated to a CQ-like aminoquinoline (AM) molecule and evaluate the potential of these PCU-AM derivatives as reversed CQ agents. PCU-AM derivatives 1-3 showed anti-plasmodial IC50 values in the ranges of 3.74-17.6 nM and 27.6-253.5 nM against CQ-sensitive (D10) and CQ-resistant strains (Dd2) of Plasmodium falciparum, respectively. Compound 1 presented with the best antiplasmodial activity at low nM concentrations against both strains and was found to be 5 fold more active against the resistant strain than CQ. Compound 1 can be considered as a lead compound to develop reversed CQ agents with improved pharmacodynamic and pharmacokinetic properties.
疟疾寄生虫对现有抗疟药（如氯喹，CQ）的耐药性增加，使疟疾的控制变得复杂。在此，我们报告了五环十一烷基胺（PCU）原型NGP1-01逆转CQ耐药性（>50%）并作为化学增敏剂的能力。基于这一发现，我们着手合成一小系列新型药物，这些药物由作为逆转剂的PCU部分与类似CQ的氨基喹啉（AM）分子共轭组成，并评估这些PCU-AM衍生物作为逆转CQ药物的潜力。PCU-AM衍生物1-3对恶性疟原虫的CQ敏感株（D10）和CQ耐药株（Dd2）的抗疟IC50值分别在3.74-17.6 nM和27.6-253.5 nM范围内。化合物1在低nM浓度下对两种菌株均表现出最佳抗疟活性，并且发现其对耐药株的活性比CQ高5倍。化合物1可被视为一种先导化合物，用于开发具有改善的药效学和药代动力学性质的逆转CQ药物。
