Synthesis and biological evaluation of new β-D-N4-hydroxycytidine analogs against SARS-CoV-2, influenza viruses and DENV-2

  • Bioorg Med Chem Lett. 2023 Mar 1:83:129174. doi: 10.1016/j.bmcl.2023.129174.
Yeon Jin An  1 ,  Se Myeong Choi  1 ,  Eun Rang Choi  1 ,  Ye Eun Nam  1 ,  Eun Woo Seo  1 ,  Soo Bin Ahn  2 ,  Yejin Jang  3 ,  Meehyein Kim  4 ,  Jong Hyun Cho  5
Affiliations
  • 1. Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan 49315, South Korea.
  • 2. Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, South Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, South Korea.
  • 3. Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, South Korea.
  • 4. Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, South Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, South Korea. Electronic address: [email protected].
  • 5. Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan 49315, South Korea; Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Busan 49201, South Korea. Electronic address: [email protected].
PMID: 36764470 DOI: 10.1016/j.bmcl.2023.129174
Abstract

Drug repurposing approach was applied to find a potent Antiviral agent against RNA viruses such as SARS-CoV-2, influenza viruses and Dengue Virus with a concise strategy of small change in parent molecular structure. For this purpose, β-D-N4-hydroxycytidine (NHC, 1) with a broad spectrum of Antiviral activity was chosen as the parent molecule. Among the prepared NHC analogs (8a-g, and 9) from uridine, β-D-N4-O-isobutyrylcytidine (8a) showed potent activity against SARS-CoV-2 (EC50 3.50 μM), Flu A (H1N1) (EC50 5.80 μM), Flu A (H3N2) (EC50 7.30 μM), Flu B (EC50 3.40 μM) and DENV-2 (EC50 3.95 μM) in vitro. Furthermore, its potency against SARS-CoV-2 was >5-fold, 3.4-fold, and 3-fold compared to that of NHC (1), MK-4482 (2), and remdesivir (RDV) in vitro, respectively. Ultimately, compound 8a was expected to be a potent inhibitor toward RNA viruses as a viral mutagenic agent like MK-4482.

Keywords
DENV-2; Influenza viruses; Nucleosides; RNA-Polymerase; SARS-CoV-2; β-D-N(4)-Hydroxycytidine; β-D-N(4)-O-Isobutyrylcytidine.