Department of Chemistry, University of Cape Town , Rondebosch, 7701 Cape Town, South Africa.
J Med Chem. 2014 Mar 27;57(6):2789-98. doi: 10.1021/jm500098s. Epub 2014 Mar 13.
A novel class of imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98% activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 × 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78%) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.
从 SoftFocus 激酶文库的全细胞筛选中鉴定出的一类新型咪唑并嘧啶类化合物被合成并评估了对 K1（多药耐药株）和 NF54（敏感株）的抗疟活性。结构-活性关系研究鉴定出了对两种菌株均具有高活性的化合物。化合物 35 对两种菌株均具有高度活性（IC50：K1 = 6.3 nM，NF54 = 7.3 nM），与青蒿琥酯相当，在体内 P. berghei 小鼠模型（Peters 4 天试验）中以 4×50 mg/kg po 给药时具有 98%的活性。化合物 35 还在体内 SCID 小鼠模型中针对 P. falciparum 进行了评估，其疗效与体外活性更为一致。此外，化合物 35 在大鼠中具有 78%的高口服生物利用度，具有良好的口服暴露量和血浆半衰期。在相同剂量下，小鼠的暴露量比大鼠低 10 倍，表明在小鼠中口服吸收和/或代谢清除率较低。
