Guangdong University of Technology, School of Chemical Engineering and Light Industry, no. 100 Waihuan Xi road Education Mega Center, Guangzhou, 510006, P. R. China.
Laboratoire de Chimie de Coordination du CNRS, LCC-CNRS, Université de Toulouse, Université Paul Sabatier, 205 route de Narbonne, BP 44099, 31077, Toulouse cedex 4, France.
ChemistryOpen. 2022 May;11(5):e202200064. doi: 10.1002/open.202200064.
The currently spreading resistance of the malaria parasite Plasmodium falciparum to artemisinin-based combination therapies makes an urgent need for new efficient drugs. Aiming to kill artemisinin-resistant Plasmodium, a series of novel hybrid drugs named Atokels were synthesized and characterized. Atokels are based on an 8-amino- or 8-hydroxyquinoline entity covalently bound to a 1,4-naphthoquinone through a polyamine linker. These drugs have been designed to target the parasite mitochondrion by their naphthoquinone moiety reminiscent of the antimalarial drug atovaquone, and to trigger a damaging oxidative stress due to their ability to chelate metal ions in order to generate redox active complexes in situ. The most effective Atokel drug shown a promising antimalarial activity (IC =622 nm on an artemisinin-resistant P. falciparum strain) and no cytotoxicity at 50 μm indicating a specific antiplasmodial mode of action.
目前，疟原虫恶性疟原虫对青蒿素类联合疗法的耐药性正在蔓延，因此迫切需要新的高效药物。为了杀死对青蒿素耐药的疟原虫，我们合成并表征了一系列名为阿托尔的新型杂合药物。阿托尔基于 8-氨基或 8-羟基喹啉实体，通过多胺接头共价连接到 1,4-萘醌。这些药物的设计旨在通过萘醌部分靶向寄生虫线粒体，类似于抗疟药物阿托喹酮，并且由于其螯合金属离子的能力而引发破坏性氧化应激，以在原位生成氧化还原活性配合物。最有效的阿托尔药物表现出有希望的抗疟活性（在青蒿素耐药的恶性疟原虫菌株上的 IC = 622nm），并且在 50μm 时没有细胞毒性，表明其具有特异性的抗疟原虫作用模式。
