Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
J Med Chem. 2014 Nov 13;57(21):8839-48. doi: 10.1021/jm500887k. Epub 2014 Oct 23.
On the basis of our recent results on a novel series of imidazopyridazine-based antimalarials, we focused on identifying compounds with improved aqueous solubility and hERG profile while maintaining metabolic stability and in vitro potency. Toward this objective, 41 compounds were synthesized and evaluated for antiplasmodial activity against NF54 (sensitive) and K1 (multidrug resistant) strains of the malaria parasite Plasmodium falciparum and evaluated for both aqueous solubility and metabolic stability. Selected compounds were tested for in vitro hERG activity and in vivo efficacy in the P. berghei mouse model. Several compounds were identified with significantly improved aqueous solubility, good metabolic stability, and a clean hERG profile relative to a previous frontrunner lead compound. A sulfoxide-based imidazopyridazine analog 45, arising from a prodrug-like strategy, was completely curative in the Plasmodium berghei mouse model at 4 × 50 mg/kg po.
基于我们最近在一系列新型咪唑并吡啶嗪类抗疟药物方面的研究成果，我们专注于寻找具有更好水溶性和 hERG 特性的化合物，同时保持代谢稳定性和体外活性。为此，我们合成了 41 种化合物，并评估了它们对 NF54（敏感）和 K1（多药耐药）株疟原虫 Plasmodium falciparum 的抗疟活性，同时评估了它们的水溶性和代谢稳定性。选择的化合物还进行了体外 hERG 活性和体内疗效测试，以评估它们在 P. berghei 小鼠模型中的疗效。与之前的先导化合物相比，几种化合物的水溶性显著提高，代谢稳定性良好，hERG 特性良好。一种基于亚砜的咪唑并吡啶嗪类似物 45，来自前药样策略，在 4×50mg/kg po 的剂量下，对 Plasmodium berghei 小鼠模型完全具有治愈作用。
