Boudhar Aicha, Ng Xiao Wei, Loh Chiew Yee, Chia Wan Ni, Tan Zhi Ming, Nosten Francois, Dymock Brian W, Tan Kevin S W
Laboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, National University of Singapore, Singapore Department of Pharmacy, National University of Singapore, Singapore.
Laboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, National University of Singapore, Singapore.
Antimicrob Agents Chemother. 2016 Apr 22;60(5):3076-89. doi: 10.1128/AAC.02476-15. Print 2016 May.
Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria.
包括青蒿素在内的抗疟疗法耐药性已成为一项重大挑战。使用能使耐药寄生虫对先前有效的疗法重新敏感的药物，可以实现获得性耐药的逆转。基于我们最初描述使耐药寄生虫对氯喹（CQ）重新敏感的新型化学逆转剂（CRA）的工作，我们在此报告新型杂合单药，作为对抗耐药疟疾的一种创新策略。将CRA支架与氯喹合成连接，可产生对一系列耐药疟原虫具有恢复效力的杂合化合物。一种优选化合物，即化合物35，对七种对氯喹和青蒿素耐药的菌株显示出广泛的活性和良好的效力。在肝细胞系和心肌细胞系中对水溶性、膜通透性和体外毒性的评估表明，化合物35具有良好的治疗窗口和有利的类药性质。本研究为CQ-CRA杂合化合物作为耐药疟疾的潜在治疗方法提供了初步支持。
