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

: Bautista‐Aguilera, O.M.; Hagenow, S.; Palomino‐Antolin, A.; Farré‐Alins, V.; Ismaili, L.; Joffrin, P.-L.; Jimeno, M.L.; Soukup, O.; Janočková, J.; Kalinowsky, L.; Proschak, E.; Iriepa, I.; Moraleda, I.; Schwed, J.S.; Martínez, A.R.; López‐Muñoz, F.; Chioua, M.; Egea, J.; Ramsay, R.R.; Marco‐Contelles, J.; Stark, H.


Angewandte Chemie. International edition 56 (2017), No.41, pp.12765-12769
ISSN: 1433-7851
ISSN: 0044-8249
ISSN: 0570-0833
ISSN: 1521-3773
Journal Article
Fraunhofer IME ()

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.