Synthesis and Antiviral Activity of Substituted 2,4-bis-aminomethyl-5-hydroxy-1H-indole-3-carboxylic Acid Ethyl Esters and their Derivatives

New substituted ethyl esters of 2,4-bis-aminomethyl-5-hydroxy-1H-indole-3-carboxylic acids, 8-aminomethyl-2-methyl-2,3-dihydro-1H,7H-[1,3]-oxazino-[5,6-e]indole-9-carboxylic acids, and members of the previously unknown 4,5-dihydro-1H-pyrrolo[4,3,2-de]isoquinolin-3-ones of 1,4-dihydropyrrolo[4,3,2-de]isoquinolin-3,6-diones were synthesized. Their cytotoxicities and antiviral activities against bovine viral diarrhea virus (BVDV), hepatitis C virus (HCV), and A/Aichi/2/69 (H3N2) were studied in vitro. These compounds were found not to be active against these viruses. The only exceptions were the hydrochlorides of the ethyl esters of 5-hydroxy-2-(dimethylaminomethyl)-1-methyl-6-pyridine-3-yl- and 5-hydroxy-2-(dimethylaminomethyl)-1-methyl-6-fluoro-1H-indole-3-carboxylic acids, which at micromolar concentrations not only produced effective suppression of influenza A/Aichi/2/69 (H3N2) virus replication in cell cultures, but also showed high in vivo efficacy in a model of influenza pneumonia in mice infected with influenza A/Aichi/2/69 (H3N2) virus at a dose of 25 mg/kg/day.