Synthesis and structure-activity relationship of novel indole acrylamide derivatives as hcv replication inhibitors

Aseries of indole acrylamide derivatives were synthesized and evaluated for their inhibitory effects on hepatitis C virus (HCV) replication. Previously, we have identified (E)-N-(4- tert-butylphenyl)-3-(5-cyano-1H-indol-3-yl)-2-methylacrylamide (6c) as one of the promising leads for anti-HCV chemotherapy. Based on the structural features of indole acrylamide, we have explored extended structure-activity relationship study using analogs with substituted indoles, various amides, and N-substitution at the indole ring. Among the newly synthesized series, 5-cyanoindole acrylamide analog with N-acetyl substitution (13c ) (EC₅₀ = 0.98 μM, CC ₅₀ = 40.74 μM, and SI = 41.6) exhibited the most potent antiviral activity with reasonable cytotoxicity in a cell-based J6/JFH1 reporter assay using Huh7.5 cells. In addition, improved water solubility of 13c compared to 6c further merits consideration of 13c as a valuable candidate for anti-HCV therapeutics development.