Design, Synthesis, and Biological Evaluation of N-Alkylated Deoxynojirimycin (DNJ) Derivatives for the Treatment of Dengue Virus Infection

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• 作者：Wenquan Yu ; Tina Gill ; Lijuan Wang ; Yanming Du ; Hong Ye ; Xiaowang Qu ; Ju-Tao Guo ; Andrea Cuconati ; Kang Zhao ; Timothy M. Block ; Xiaodong Xu ; Jinhong Chang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：July 12, 2012
• 年：2012
• 卷：55
• 期：13
• 页码：6061-6075
• 全文大小：825K
• 年卷期：v.55,no.13(July 12, 2012)
• ISSN：1520-4804

文摘

We recently described the discovery of oxygenated N-alkyl deoxynojirimycin (DNJ) derivative 7 (CM-10鈥?8) with antiviral activity against dengue virus (DENV) infection both in vitro and in vivo. This imino sugar was promising but had an EC₅₀ against DENV in BHK cells of 6.5 渭M, which limited its use in in vivo. Compound 7 presented structural opportunities for activity relationship analysis, which we exploited and report here. These structure鈥揳ctivity relationship studies led to analogues 2h, 2l, 3j, 3l, 3v, and 4b鈥?b>4c with nanomolar antiviral activity (EC₅₀ = 0.3鈥?.5 渭M) against DENV infection, while maintaining low cytotoxicity (CC₅₀ > 500 渭M, SI > 1000). In male Sprague鈥揇awley rats, compound 3l was well tolerated at a dose up to 200 mg/kg and displayed desirable PK profiles, with significantly improved bioavailability (F = 92 卤 4%).