Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3 R Antagonism for Neurodegenerative Diseases.

Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3 R Antagonism for Neurodegenerative Diseases.

Angewandte Chemie (International ed. in English) (2017-09-02)

Óscar M Bautista-Aguilera, Stefanie Hagenow, Alejandra Palomino-Antolin, Víctor Farré-Alins, Lhassane Ismaili, Pierre-Louis Joffrin, María L Jimeno, Ondřej Soukup, Jana Janočková, Lena Kalinowsky, Ewgenij Proschak, Isabel Iriepa, Ignacio Moraleda, Johannes S Schwed, Alejandro Romero Martínez, Francisco López-Muñoz, Mourad Chioua, Javier Egea, Rona R Ramsay, José Marco-Contelles, Holger Stark

PMID28861918

摘要

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.