Influence of the γ-carboline and carbazole pharmacophore moieties on anticholinesterase and antiradical activity of multifunctional agents for the treatment of neurodegenerative diseases

Abstract

A comparative analysis of the esterase profile and antiradical activity of two groups of hybrid compounds, viz., tetrahydro-γ-carboline conjugates with carbazoles and tetrahydrocarbazoles (I) and carbazole conjugates with carbazoles and tetrahydrocarbazoles (II), was performed. The replacement of the tetrahydro-γ-carboline moiety (conjugates I) by the carbazole group (conjugates II) was shown to significantly reduce the ability of the compounds to inhibit butyrylcholinesterase (BChE) and scavenge free radicals. The tetrahydro-γ-carboline–tetrahydrocarbazole combination is optimal in terms of both high anti-BChE activity and free radical scavenging ability. According to molecular modeling calculations, the stronger binding of tetrahydro-γ-carboline conjugates (I) in the BChE active site compared to carbazole conjugates (II) is attributed to the ability of I to form ionic and π-cation interactions with amino acid residues lining the BChE gorge. Therefore, conjugates of tetrahydro-γ-carboline and tetrahydrocarbazole derivatives are the most promising compounds for the design of new multitarget drugs combining cognitive-stimulating and antioxidant properties.