Design and evaluation of novel tetracyclic benzofurans as palm site allosteric inhibitors of HCV NS5B polymerase.

•N-linked and C-linked tetracyclic benzofuran-based compounds were made and evaluated as HCV 5B non-nucleoside inhibitors.•Tetracyclic benzofuran-based structures maintained broad spectrum anti-replicon potency profiles.•Compounds demonstrated moderate to excellent oral bioavailability and pharmacokinetic parameters.•C-linked tetracycle with 6-number ring displayed improved solubility and permeability compared to a clinical compound.