Synthesis of novel 6-azacytidine prodrugs as potent influenza A inhibitors.

We report the synthesis and evaluation of novel prodrugs of 6-azacytidine (6-AzaCyd) to identify potent and bioavailable inhibitors of influenza A viruses. Prodrug N4-2-propylpentanamide 6-AzaCyd 6a was identified, through a nucleoside prodrug strategy, with a promising potency profile [H1N1-EC90 = 2.6 μM, VTR = 3 at 10 μM; H3N2-EC90 = 3.5 μM, VTR = 2.8 at 10 μM in MDCK cells; EC50 = 2.1 μM from cap snatching polymerase U2-PB2 assay; cytotoxicity CC50 > 40 μM in A549 cells; CC50 > 20 μM in MDCK cells] and an acceptable absorption, distribution, metabolism and excretion (ADME) profile [mouse liver microsome (MLM) t1/2 = 105 min, human liver microsome (HLM) t1/2 = 65 min, Solubility = 77 μM]. Compound 6a also exhibited acceptable pharmacokinetic properties via intraperitoneal (i.p.) route of administration. The details for the synthesis of 6-AzaCyd prodrugs and anti-influenza A activity are described herein.