Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 2

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• 作者：Claire Le Manach ; Tanya Paquet ; Diego Gonz脿lez Cabrera ; Yassir Younis ; Dale Taylor ; Lubbe Wiesner ; Nina Lawrence ; Sylva Schwager ; David Waterson ; Michael J. Witty ; Sergio Wittlin ; Leslie J. Street ; Kelly Chibale
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：November 13, 2014
• 年：2014
• 卷：57
• 期：21
• 页码：8839-8848
• 全文大小：473K
• ISSN：1520-4804

文摘

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 脳 50 mg/kg po.