Synthesis And Antiviral Activities Of Ethyl 5-Hydroxy-1H-Indole-3-Carboxylates

The viral respiratory tract infection is the most common viral infectious disease in human. In this paper we focused largely on the biological characteristics of influenza virus, respiratory syncytical virus (RSV) and coronavirus and pointed out the suitable antiviral targets in their replication cycles for chemotherapeutic intervention. The development of antiviral agents against influenza virus, RSV and severe acute respiratory syndrome associated coronavirus (SARS-CoV) was also introduced respectively.Arbidol, an ethyl 5-hydroxy-1H-indole-3-carboxylate derivative, was launched in the Russian Federation for the prophylaxis and treatment of influenza A and B and other acute respiratory viral infections. Arbidol also inhibited other respiratory tract viruses such as RSV and SARS-CoV. Taking Arbidol as lead compound, modifications and optimi--zations were made at 1-position, 2-position and 4-position on the indole ring. Total 65 target compounds were designed and synthesized, and their structures were confirmed by IR, MS and 1H-NMR. Among them, 64 compounds were not reported in literatures.The antiviral activities of these target compounds against influenza A3 and RSV Long strains were evaluated with cytopathic effect assay in MDCK and HeLa cells respectively. Some of them were found to exhibit potent and selective inhibitory effects on influenza virus and RSV, which were comparable to (or slightly more potent than) Arbidol (IC50 3.9 ug/mL, TI 32). Compound GZ01, GZ02, GZ07, GZ08, GZ17, GZ29, GZ31, GZ32, GZ34, GZ37 and GZ40 all had remarkable antiviral activity and high selectivity(IC 50 3.9 ug/mL, TI 256).The antiviral activity of these target compounds against SARS-CoV BJ-01 strain wasevaluated with MTS colorimetric assay in Vero cells. All of them exhibited different level antiviral activity. Among them, compound GZ09, GZ12, GZ21, GZ23, GZ24, GZ25, GZ30, GZ31, GZ32, GZ64 and GZ65 were highly active inhibitors with the inhibitory percentage more than 80%.The structure-activity relationships between these ethyl 5-hydroxy-1H-indole-3-carboxylates and their antiviral activities against influenza virus, RSV, SARS-CoV were discussed, which would provide useful information for the research and development of new type antiviral agents in the future.