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Platinum(II)-chloroquine complexes are antimalarial agents against blood and liver stages by impairing mitochondrial function
Metallomics ( IF 2.9 ) Pub Date : 2017-09-19 00:00:00 , DOI: 10.1039/c7mt00196g
Taís S. Macedo 1, 2, 3, 4 , Wilmer Villarreal 4, 5, 6, 7 , Camila C. Couto 1, 2, 3, 4 , Diogo R. M. Moreira 1, 2, 3, 4 , Maribel Navarro 4, 6, 8, 9, 10 , Marta Machado 11, 12, 13, 14, 15 , Miguel Prudêncio 11, 12, 13, 14, 15 , Alzir A. Batista 4, 5, 6, 7 , Milena B. P. Soares 1, 2, 3, 4, 16
Affiliation  

Chloroquine is an antimalarial agent with strong activity against the blood stage of Plasmodium infection, but with low activity against the parasite’s liver stage. In addition, the resistance to chloroquine is limiting its clinical use. Finding new molecules possessing a multistage activity and overcoming drug resistance is needed. One possible strategy to achieve this lies in combining antimalarial quinolones with the pharmacological effects of transition metals. We investigated the antimalarial activity of four platinum(II) complexes composed of chloroquine and phosphine ligands, denoted WV-90, WV-92, WV-93 and WV-94. In comparison to Chloroquine, complexes were less potent against the chloroquine-sensitive 3D7 strain but they were as active as in inhibiting the chloroquine-resistant W2 strain of P. falciparum. Regarding selectivity, the complexes WV-90 and WV-93 displayed the higher indexes. Unlike chloroquine, complexes act as irreversible parasiticidal agents against trophozoites and WV-93 complex displayed activity against the hepatic stage of P. berghei. The in vivo suppression activity against P. berghei in the Peters 4-day test displayed by the complexes was similar to that of chloroquine. However, efficacy in an established P. berghei infection in the Thompson test was superior for WV-93 complex than chloroquine. The complexes’ antimalarial mechanism of action is initiated by inhibiting the hemozoin formation. While chloroquine efficiently inhibits hemozoin, parasites treated with platinum complexes displayed residual hemozoin crystals. This is explained since platinum complexes interaction with ferriprotoporphyrin is weaker than chloroquine. However, complexes caused a loss of mitochondrial integrity and subsequent reduction of its activity, and their effects on mitochondria were more pronounced than chloroquine-treated parasites. The dual effect of platinum complexes may explain their activity against the hemozoin-lacking parasites (hepatic stage), where chloroquine has no activity. Our findings support that platinum(II)-chloroquine complexes are multifunctional antimalarial compounds and reinforce the importance of metal complexes in antimalarial drug discovery.

中文翻译:

铂(II)-氯喹配合物是通过破坏线粒体功能来对抗血液和肝脏阶段的抗疟药

氯喹是抗疟疾药,对疟原虫感染的血液阶段具有较强的活性,而对寄生虫的肝脏阶段具有较低的活性。另外,对氯喹的抗性限制了其临床用途。需要寻找具有多阶段活性并克服耐药性的新分子。实现这一目标的一种可能策略是将抗疟药喹诺酮类与过渡金属的药理作用相结合。我们研究了由氯喹和膦配体组成的四种铂(II)配合物的抗疟活性,分别为WV-90,WV-92,WV-93和WV-94。与氯喹相比,复合物对氯喹敏感的3D7菌株的效力较弱,但与抑制恶性疟原虫耐氯喹的W2菌株一样有效。关于选择性,WV-90和WV-93配合物显示较高的指数。与氯喹不同,络合物可作为对抗滋养体的不可逆杀虫剂,而WV-93络合物则具有针对伯氏疟原虫肝阶段的活性。配合物显示的Peters 4天试验中对柏氏疟原虫的体内抑制活性与氯喹相似。然而,在汤普森试验中,在已确定的伯氏疟原虫感染中,WV-93复合物的疗效优于氯喹。该复合物的抗疟疾作用机制是通过抑制hezozoin的形成而启动的。尽管氯喹有效抑制血红蛋白,但用铂配合物处理的寄生虫显示出残留的血红蛋白晶体。可以解释这是因为铂络合物与亚铁原卟啉的相互作用比氯喹弱。然而,复合物导致线粒体完整性的丧失并随后降低了其活性,它们对线粒体的影响比氯喹处理的寄生虫更为明显。铂配合物的双重作用可能解释了它们对缺乏血凝素的寄生虫(肝阶段)的活性,氯喹没有活性。我们的发现支持铂(II)-氯喹配合物是多功能的抗疟化合物,并增强了金属配合物在抗疟药物发现中的重要性。
更新日期:2017-09-20
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