| Literature DB >> 28861918 |
Óscar M Bautista-Aguilera1, Stefanie Hagenow2, Alejandra Palomino-Antolin3, Víctor Farré-Alins3, Lhassane Ismaili4, Pierre-Louis Joffrin5, María L Jimeno1, Ondřej Soukup6, Jana Janočková6, Lena Kalinowsky7, Ewgenij Proschak7, Isabel Iriepa8, Ignacio Moraleda8, Johannes S Schwed2, Alejandro Romero Martínez9, Francisco López-Muñoz10, Mourad Chioua1, Javier Egea3, Rona R Ramsay5, José Marco-Contelles1, Holger Stark2.
Abstract
The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg-1 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.Entities:
Keywords: antioxidants; drug design; inhibitors; multitarget drugs; neurological agents
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Year: 2017 PMID： 28861918 DOI： 10.1002/anie.201706072
Source DB: PubMed Journal: Angew Chem Int Ed Engl ISSN： 1433-7851 Impact factor: 15.336