Potent inhibitors of hepatitis C core dimerization as new leads for anti-hepatitis C agents

Abstract

New indoline alkaloid-type compounds which inhibit HCV production by infected hepatoma cells have been identified. These compounds, dimeric-type compounds of previously known inhibitors, display double digit nanomolar IC(50) and EC(50) values, with cytotoxicity CC(50) indexes higher than 36 μM, thus providing ample therapeutic windows for further development of HCV drugs.

Figure 1

Previously reported inhibitors of core dimerization.

Figure 1

Dose-response analyses of 20 using Core106 ALPHA screen assay. The compound was dosed from 0 to 100 µM; IC₅₀ and EC₅₀’s were calculated using a non-linear regression ‘Log[inhibitor] vs response’ with four points per concentration. (A) IC₅₀; (B) T1-EC₅₀; (C) T2-EC₅₀.

Scheme 1

Dimerization of 2 through metathesis.

Scheme 2

Preparation of dimer 11 with an ether linkage between the monomeric subunits.

Scheme 3

Preparation of dimers 14 and 15 with all-carbon tethers linking the monomeric subunits.

Scheme 4

Preparation of tethered bis-heterocycles 20 and 21 via Click dipolar addition chemistry.