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Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3R Antagonism for Neurodegenerative Diseases

AuthorsBautista-Aguilera, Óscar M.; Hagenow, S.; Palomino-Antolin, A.; Farré-Alins, V.; Ismaili, L.; Joffrin, P. L.; Jimeno, M. Luisa; Soukup, O.; Janockova, Jana; Kalinowski, A.; Proschak, E.; Iriepa, Isabel; Moraleda, I.; Schwed, J. S.; Romero Martínez, Alejandro; López-Muñoz, Francisco; Chioua, Mourad ; Egea, Javier; Ramsay, R. R.; Marco-Contelles, José ; Stark, H.
KeywordsMultitarget drugs
Neurological agents
Drug design
Issue Date2017
PublisherJohn Wiley & Sons
CitationAngewandte Chemie International Edition 56: 12765-12769 (2017)
AbstractThe 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 H 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 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.
Publisher version (URL)http://dx.doi.org/10.1002/anie.201706072
Identifiersdoi: 10.1002/anie.201706072
issn: 1433-7851
e-issn: 1521-3773
Appears in Collections:(IQOG) Artículos
(CENQUIOR) Artículos
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