Indole derivatives as dual-effective agents for the treatment of neurodegenerative diseases: Synthesis, biological evaluation, and molecular modeling studies

Several indole derivatives, that were highly potent ligands of GluN2B-subunit-containing N-methyl-d-aspartate (NMDA) receptor, also demonstrated antioxidant properties in ABTS method. In particular, the 2-(4-benzylpiperidin-1-yl)-1-(5-hydroxy-1H-indol-3-yl)ethanone (1) proved to be a dual-effective neuroprotective agent. With the aim to increase the antioxidant properties we added a catechol moiety onto piperidine moiety. The designed hybrid derivative 3,4-dihydroxy-N-[1-[2-(5-hydroxy-1H-indol-3-yl)-2-oxoethyl]piperidin-4-yl]benzamide (10) was the most effective antioxidant agent (>94.1 ± 0.1% of inhibition at 17 μM) and showed GluN2B/NMDA receptor affinity at low micromolar concentration (IC50 0.66 μM). By means of computational studies we explored the effect of the presence of this antioxidant fragment during the recognition process to binding pocket.