Synthesis and biological evaluation in vitro and in mammalian cells of new heteroaryl carboxyamides as HIV-protease inhibitors

Abstract

New heteroaryl HIV-protease inhibitors bearing a carboxyamide spacer were synthesized in few steps and high yield, from commercially available homochiral epoxides. Different substitution patterns were introduced onto a given isopropanoyl-sulfonamide core modifying the type of heteroarene and the central core, with the presence of either H or benzyl group. Their in vitro inhibition activity against recombinant protease showed a general beneficial effect of carboxyamide moiety, the IC₅₀ values ranging between 1 and 15nM. In particular benzofuryl derivatives showed IC₅₀ values among the best for such structurally simple inhibitors. Docking analysis allowed to identify the favorable situation of such benzofuryl derivatives in terms of number of interactions in the active site, supporting the experimental results on activity. The inhibition activity of such molecules has been also evaluated in HEK293 cells expressing the protease fused to green fluorescent protein, by western blotting analysis, fluorescence microscopy and cytofluorimetry.