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

We recently described the discovery of oxygenated N-alkyl deoxynojirimycin (DNJ) derivative 7(CM-10–18) with antiviral activity against dengue virus (DENV)infection both in vitro and in vivo. This imino sugar was promisingbut had an EC50against DENV in BHK cells of 6.5 μM,which limited its use in in vivo. Compound 7presentedstructural opportunities for activity relationship analysis, whichwe exploited and report here. These structure–activity relationshipstudies led to analogues 2h, 2l, 3j, 3l, 3v, and 4b–4cwith nanomolar antiviral activity (EC50= 0.3–0.5μM) against DENV infection, while maintaining low cytotoxicity(CC50> 500 μM, SI > 1000). In male Sprague–Dawleyrats, compound 3lwas well tolerated at a dose up to200 mg/kg and displayed desirable PK profiles, with significantlyimproved bioavailability (F= 92 ± 4%). [ABSTRACT FROM AUTHOR]