Synthesis and biological evaluation of new β-D-N(4)-hydroxycytidine analogs against SARS-CoV-2, influenza viruses and DENV-2

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-N(4)-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-N(4)-O-isobutyrylcytidine (8a) showed potent activity against SARS-CoV-2 (EC(50) 3.50 μM), Flu A (H1N1) (EC(50) 5.80 μM), Flu A (H3N2) (EC(50) 7.30 μM), Flu B (EC(50) 3.40 μM) and DENV-2 (EC(50) 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.