GlaxoSmithKline Research Centre Zagreb Ltd., Zagreb, Croatia.
Center for Translational and Clinical Research, Department for Intercellular Communication, University of Zagreb School of Medicine, Zagreb, Croatia.
Br J Pharmacol. 2021 Jan;178(2):363-377. doi: 10.1111/bph.15292. Epub 2020 Dec 16.
Efficacy of current antimalarial treatments is declining as a result of increasing antimalarial drug resistance, so new and potent antimalarial drugs are urgently needed. Azithromycin, an azalide antibiotic, was found useful in malaria therapy, but its efficacy in humans is low.
Four compounds belonging to structurally different azalide classes were tested and their activities compared to azithromycin and chloroquine. in vitro evaluation included testing against sensitive and resistant Plasmodium falciparum, cytotoxicity against HepG2 cells, accumulation and retention in human erythrocytes, antibacterial activity, and mode of action studies (delayed death phenotype and haem polymerization). in vivo assessment enabled determination of pharmacokinetic profiles in mice, rats, dogs, and monkeys and in vivo efficacy in a humanized mouse model.
Novel fast-acting azalides were highly active in vitro against P. falciparum strains exhibiting various resistance patterns, including chloroquine-resistant strains. Excellent antimalarial activity was confirmed in a P. falciparum murine model by strong inhibition of haemozoin-containing trophozoites and quick clearance of parasites from the blood. Pharmacokinetic analysis revealed that compounds are metabolically stable and have moderate oral bioavailability, long half-lives, low clearance, and substantial exposures, with blood cells as the preferred compartment, especially infected erythrocytes. Fast anti-plasmodial action is achieved by the high accumulation into infected erythrocytes and interference with parasite haem polymerization, a mode of action different from slow-acting azithromycin.
The hybrid derivatives described here represent excellent antimalarial drug candidates with the potential for clinical use in malaria therapy.
由于抗疟药物耐药性的增加，当前抗疟药物的疗效正在下降，因此急需新的、有效的抗疟药物。阿奇霉素是一种氮杂内酯类抗生素，在疟疾治疗中被证明是有效的，但在人体中的疗效较低。
测试了四种属于结构不同氮杂内酯类的化合物，并将其与阿奇霉素和氯喹进行了比较。体外评估包括对敏感和耐药性疟原虫的检测、对 HepG2 细胞的细胞毒性、在人红细胞中的积累和保留、抗菌活性以及作用机制研究（延迟死亡表型和血红蛋白聚合）。体内评估使我们能够确定在小鼠、大鼠、狗和猴子中的药代动力学特征以及在人源化小鼠模型中的体内疗效。
新型快速作用的氮杂内酯类化合物对表现出各种耐药模式的疟原虫菌株具有高度的体外活性，包括对氯喹耐药的菌株。在疟原虫小鼠模型中，通过强烈抑制含血红素的滋养体和快速清除血液中的寄生虫，证实了其具有良好的抗疟活性。药代动力学分析表明，化合物代谢稳定，具有中等的口服生物利用度、较长的半衰期、较低的清除率和较高的暴露量，血细胞是首选的药物分布部位，特别是感染的红细胞。快速抗疟作用是通过高浓度进入感染的红细胞和干扰寄生虫血红蛋白聚合来实现的，这是一种与缓慢作用的阿奇霉素不同的作用机制。
本文描述的杂交衍生物是极好的抗疟药物候选物，具有在疟疾治疗中临床应用的潜力。
