Synthesis and evaluation of the anti-hepatitis B virus activity of 4'-Azido-thymidine analogs and 4'-Azido-2'-deoxy-5-methylcytidine analogs: structural insights for the development of a novel anti-HBV agent

Abstract

Hepatitis B virus (HBV) infection is a major worldwide health problem that requires the development of improved antiviral therapies. Here, a series of 4'-Azido-thymidine/4'-Azido-2'-deoxy-5-methylcytidine derivatives (6, 10-15) were synthesized, and their anti-HBV activities evaluated. Compounds 10-15 were synthesized via an S_NAr reaction of 18, in which the 4-position of the thymine moiety was activated as the 2,4,6-triisopropylbenzenesulfonate. Compounds 11-15 showed no antiviral activity. However, 4'-Azido thymidine (6) and 4'-Azido-2'-deoxy-5-methylcytidine (10) displayed significant anti-HBV activity (EC₅₀ = 0.63 and 5.99 µM, respectively) with no detectable cytotoxicity against MT-2 cells up to 100 µM.

Keywords: 4′-azido nucleoside; Anti-HBV nucleoside; modified pyrimidines.

Figure 1.

Structures of compounds 1–5.

Figure 2.

Structures of compounds 6–15.

Scheme 1.

Synthesis of 4′-azido-4-substituted pyrimidine nucleosides 10–15. Reagents and conditions: (i) m-CBA, m-CPBA, K₂HPO₄, nBu₄NHSO₄, DCM/H₂O; (ii) 2,4,6-triisopro-pylbenzenesulfonyl chloride, TEA, DMAP, DCM; (iii) 1,4-diazabicyclo[2.2.2]octane, DBU, ROH, rt, overnight, then NH₃/MeOH, 50 °C, overnight; (iv) RNH₂, solvent, 50 °C, overnight, then NH₃/MeOH, 50 °C, overnight.