Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Avenue, Tampa, Florida 33620, United States.
J Med Chem. 2011 Dec 22;54(24):8321-7. doi: 10.1021/jm200718m. Epub 2011 Nov 23.
ICI 56,780 (5) displayed causal prophylactic and blood schizonticidal activity (ED50=0.05 mg/kg) in rodent malaria models but produced rapid acquisition of parasitological resistance in P. berghei infected mice. Herein we describe the synthesis of analogues of 5 with EC50 as low as 0.15 nM against multidrug resistant P. falciparum. Optimal activity with low cross-resistance indexes (RI) to atovaquone was achieved by introducing ortho-substituted aryl moieties at the 3-position of the 7-(2-phenoxyethoxy)-4(1H)-quinolone core.
ICI 56,780(5)在啮齿动物疟疾模型中表现出因果预防和血裂殖体杀活性(ED50=0.05mg/kg),但在感染伯氏疟原虫的小鼠中迅速产生寄生虫学抗性。在此,我们描述了 5 的类似物的合成,其对多药耐药性恶性疟原虫的 EC50 低至 0.15nM。通过在 7-(2-苯氧基乙氧基)-4(1H)-喹诺酮核心的 3 位引入取代的芳基取代基,实现了与阿托伐醌的低交叉抗性指数(RI)的最佳活性。