2. Academic Validation
  3. Synthesis of novel 6-azacytidine prodrugs as potent influenza A inhibitors

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

  • Bioorg Med Chem Lett. 2026 Feb 1:131:130473. doi: 10.1016/j.bmcl.2025.130473.
Omar Moukha-Chafiq 1,  Larry D Bratton 2,  Shuklendu D Karyakarte 2,  Kathy Keith 3,  Yohanka Martinez-Gzegozewska 2,  Sarath C Sarngadharan 2,  Lynn Rasmussen 2,  Bob Bostwick 2,  Ashish K Pathak 2,  Richard Whitley 3,  Corinne E Augelli-Szafran 2
Affiliations

Affiliations

  • 1 Scientific Platforms, Southern Research, 2000 Ninth Avenue South, Birmingham, AL 35205, USA. Electronic address: moukha@uab.edu.
  • 2 Scientific Platforms, Southern Research, 2000 Ninth Avenue South, Birmingham, AL 35205, USA.
  • 3 Department of Paediatrics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
PMID: 41242348 DOI: 10.1016/j.bmcl.2025.130473
Abstract

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.

Keywords

6-Azacytidine; Influenza A inhibition; Nucleoside prodrug approach.

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