An Efficient, Short Synthesis, and Potent Anti-Hepatitis B Viral Activity of a Novel Ring-Expanded Purine Nucleoside Analogue Containing a 5:7-Fused, Planar, Aromatic, Imidazo[4,5-E][1,3]diazepine Ring System

Abstract An efficient, short synthesis of a ring-expanded nucleoside analogue containing a novel 5:7-fused, planar, and potentially aromatic imidazo[4,5-e][1,3]diazepine heterocyclic ring system is reported. The target compound, 6-amino-8-hydroxy-4H-1-β-D-ribofuranosylimidazo[4,5-e][1,3]diazepin-4-one (2) was synthesized in a single step in ⩾90% yield by condensation of guanidine with either methyl 1-β-D-ribofuranosylimidazole-4,5-dicarboxylate (1a) or its 2′,3′,5′-tri-O-benzoyl derivative (1b). Compound 2 showed potent anti-hepatitis B virus (anti-HBV) activity with an EC50 value of 0.17 μM in the transfected hepatoma cell line 2.2.15, and a low cellular toxicity with a CC50 value of 2.4 mM (TI > 14,000).