Structure鈥揂ctivity-Relationship Studies around the 2-Amino Group and Pyridine Core of Antimalarial 3,5-Diarylaminopyridines Lead to a Novel Series of Pyrazine Analogues with Oral in Vivo Activity

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• 作者：Yassir Younis ; Frederic Douelle ; Diego Gonz谩lez Cabrera ; Claire Le Manach ; Aloysius T. Nchinda ; Tanya Paquet ; Leslie J. Street ; Karen L. White ; K. Mohammed Zabiulla ; Jayan T. Joseph ; Sridevi Bashyam ; David Waterson ; Michael J. Witty ; Sergio Wittlin ; Susan A. Charman ; Kelly Chibale
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8860-8871
• 全文大小：634K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

Replacement of the pyridine core of antimalarial 3,5-diaryl-2-aminopyridines led to the identification of a novel series of pyrazine analogues with potent oral antimalarial activity. However, other changes to the pyridine core and replacement or substitution of the 2-amino group led to loss of antimalarial activity. The 3,5-diaryl-2-aminopyrazine series showed impressive in vitro antiplasmodial activity against the K1 (multidrug resistant) and NF54 (sensitive) strains of Plasmodium falciparum in the nanomolar IC₅₀ range of 6鈥?4 nM while also demonstrating good in vitro metabolic stability in human liver microsomes. In the Plasmodium berghei mouse model, this series generally exhibited good efficacy at low oral doses. One of the frontrunner compounds, 4, displayed potent in vitro antiplasmodial activity with IC₅₀ values of 8.4 and 10 nM against the K1 and NF54 strains, respectively. When evaluated in P. berghei-infected mice, compound 4 was completely curative at an oral dose of 4 脳 10 mg/kg.