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

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