title: Indole derivatives as dual-effective agents for the treatment of neurodegenerative diseases: synthesis, biological evaluation, and molecular modeling studies.
abstract: 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.
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università di Messina, Viale Annunziata, Messina I-98168, Italy.
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Buemi
authors.forename: Laura
authors.initials: L
authors.lastname: De Luca
authors.forename: Alba
authors.initials: A
authors.lastname: Chimirri
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferro
authors.forename: Rosaria
authors.initials: R
authors.lastname: Gitto
authors.forename: Julio
authors.initials: J
authors.lastname: Alvarez-Builla
authors.forename: Ramon
authors.initials: R
authors.lastname: Alajarin
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D011869:Radioligand Assay; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000975:Antioxidants; D007211:Indoles; D016194:Receptors, N-Methyl-D-Aspartate