Synthesis And In Vitro Antiviral Activities Against Influenza Viruses Of Ethyl 5-Hydroxy-6-Bromo-1H-Indole-3-Carboxylate Derivatives

Influenza is an acute respiratory tract infection caused by influenza A and B viruses and it remains a serious seasonal health concern. The antiviral activity of Arbidol, a new antiviral agent, is most pronounced against influenza viruses of the A and B antigenic type. Its effect may be due to activation of 2,5-oligoadenylate synthetase. Arbidol has been developed and licensed for the treatment and prophylaxis of influenza and other acute respiratory viral infections.Derivatives of 5-hydroxy-6-bromo-lH-indole-3-carboxylic acid ethyl ester, analogs of arbidol, were reported to possess antiviral activity for influenza viruses in vitro and in animal models of influenza virus infection. Hence, with arbidol as the leading compound, it was thought of considerable interest to synthesize its new analogs to evaluate their antiviral activities. Based on the structure of arbidol, some modifications were made at the 1 positon, the 2 positon and the 4 position of indole nucleus. Total 64 compouds, respectively bearing three kinds of different structural skeletones: ethyl l-alkyl-2-phenyl thiomethyl-4-substitutedaminomethyl-5-hydroxy-6-bromo-1H-indole-3-carboxylate ( in brief, 4-substitutedaminomethyl-lH-indole ) , ethyl l-alkyl-2-heteroarylthiomethyl-4-substitutedaminomethyl-5-hydroxy-6-bromo-lH-indole-3-carboxylate (in brief, 2-hetero arylthiomethyl-1H-indole ) , ethyl l-alkyl-2-phenylthiomethyl-4-guanidinylmethyl-5-hydroxy-6-bromo-lH- indole-3-carboxylate(in brief, 4-guanidinylmethyl-lH-indole), were synthesized and their chemical structures were confirmed by 1H-NMR 13C-NMR and MS, and among them 63 compouds have been not reported in literatures.The activities of these compounds in vitro against laboratory-passaged isolates of human influenza A3 and respiratory syncytial virus (RSV) were examined, respectively in MDCK cell culture and HeLa cell culture with virus cytopathic effect assay in comparison with amantadine, ribavirin and arbidol.Out of 50 tested derivatives of 4-substitutedaminomethyl-lH-indole, 16 compouds showed active virus-inhibitory activity with therapeutic index (TI) not less than 64. Among them, compouds A43 and A53 were the most effective inhibitors. Compoud A43gave inhibitory effects against influenza A3 virus and RSV virus with 50% inhibitory concentrations (IC50) both below 3.9 g mL-1 and TI both of 513 higher than control drugs amantadine and arbidol, while compoud A53 have the least IC50 values of 1.47 gmL-1, 0.81 g mL-1 and TI values of 341, 855 respectively against the above two employed viruses.Derivatives of 2-heteroarylthiomethyl-lH-indole generally exhibited weak antiviral activities except for compoud B2, which possessed the most potent antiviral activity among all tested compounds with IC50 less than 3.9 gmL-1 and TI as high as 1026 both for influenza A3 virus and RSV virus.Derivatives of 4-guanidinylmethyl-lH-indole also showed potent abilities to inhibit cytopathic effect by influenza A3 virus and RSV virus.The structure-activity relationships of the compounds mentioned above have been explored, which may make theoretical and practical bases for future work on the project searching for more potential leading compoud.