New Heterocyclic Hepatitis C Virus (HCV) Inhibitors Containing A 2-Aminomethyl-1H-Indole Fragment

A focused library of heterocyclic compounds including a 2-aminomethyl-1H-benzimidazole (1 – 19), 2-aminomethylindole (20 – 83), benzofuran-2-ylmethylamine (84 – 92), or 2-piperazin-1-ylmethylbenzoxazole (93) fragment was screened for the ability to inhibit in vitro hepatitis C virus (HCV). The synthetic methods were described. The antiviral activity and cytotoxicity data were presented. Most of the compounds carrying a benzoxazol-2-ylmethylamine fragment inhibited Huh7.3 human hepatoma cells infected in vitro with HCV with nanomolar potency but were inactive against the HCV RNA-replicon. The only exception was 9-methyl-N(6)-(3-nitrophenyl)-2,3,4,9-tetrahydro-1H-carbazole-1,6-diamine (67), which demonstrated nanomolar potency against HCV in both models. The most active and selective compounds were (piperazin-1-yl)-[(1Hindol-2-ylmethyl)piperidin-4-yl]-ketones (EC₅₀ 0.31 – 2.2 μM, CC₅₀ 10.2-110 μM) and 2-(1,2,3a,4,5,6-hexahydropyrazino[3,2,1-jk]carbazol-3-yl)acetamide (EC₅₀ 1.69 ± 0.5 μM, CC₅₀ 114 ± 42 μM). The two most selective inhibitors (28, TI₅₀ = 52 and 77, TI₅₀ = 68) were selected for further preclinical trials.