iMed.UL-Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
Antimicrob Agents Chemother. 2011 Oct;55(10):4698-706. doi: 10.1128/AAC.05133-11. Epub 2011 Aug 1.
It is widely accepted that the struggle against malaria depends on the development of new strategies to fight infection. The "magic bullet" thought to be necessary to reach eradication should not only provide treatment for all Plasmodium spp. that infect human red blood cells but should also eliminate the replicative and dormant liver forms of the parasite. Moreover, these goals should ideally be achieved by using different mechanisms of action so as to avoid the development of resistance. To that end, two hybrid molecules with covalently linked primaquine and artemisinin moieties were synthesized, and their effectiveness against the liver and blood stages of infection was compared in vitro and in vivo with those of the parent compounds. Both hybrids displayed enhanced in vitro activities, relative to those of the parent compounds, against Plasmodium berghei liver stages. Both compounds were about as potent as artemisinin against cultured Plasmodium falciparum (50% inhibitory concentration [IC(50)], ∼10 nM). When used to treat a murine P. berghei infection, one of the molecules displayed better efficacy than an equimolar mixture of the parent pharmacophores, leading to improved cure and survival rates. These results reveal a novel approach to the design and evaluation of antimalarials based on the covalent combination of molecules acting on different stages of the parasite life cycle.
人们普遍认为,抗击疟疾取决于开发新的策略来对抗感染。被认为是达到消除所必需的“灵丹妙药”不仅要为所有感染人类红细胞的疟原虫提供治疗,而且还要消除寄生虫的复制和休眠肝脏形式。此外,这些目标最好通过使用不同的作用机制来实现,以避免耐药性的发展。为此,合成了两种具有共价连接的 primaquine 和 artemisinin 部分的杂交分子,并在体外和体内比较了它们对感染的肝和血期的有效性与母体化合物的比较。两种杂种在体外对伯氏疟原虫肝期的活性均相对于母体化合物增强。两种化合物对培养的恶性疟原虫(50%抑制浓度[IC(50)],约 10 nM)的活性与 artemisinin 一样强。当用于治疗鼠疟原虫感染时,其中一种分子的疗效优于母体药效团的等摩尔混合物,从而提高了治愈率和存活率。这些结果揭示了一种基于作用于寄生虫生命周期不同阶段的分子的共价结合来设计和评估抗疟药物的新方法。