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

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

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: mkim@krict.re.kr.
  • 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: jhcho1@dau.ac.kr.
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.

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