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Angew Chem Int Ed Engl. 2017 Oct 2;56(41):12765-12769. doi: 10.1002/anie.201706072. Epub 2017 Sep 1.

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

Author information

1
Laboratorio de Química Médica, Instituto de Química Orgánica General, CSIC and Centro de Química Orgánica "Lora-Tamayo", CSIC, C/ Juan de la Cierva 3, 28006, Madrid, Spain.
2
Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225, Düsseldorf, Germany.
3
Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Calle de Diego de León, 62, 28006, Madrid, Spain.
4
Neurosciences Intégratives et Cliniques EA 481, Université Bourgogne Franche-Comté, Rue Ambroise Paré, 25000, Besançon, France.
5
Biomedical Sciences Research Complex, University of St Andrews, Biomolecular Sciences Building, North Haugh, St Andrews, KY16 9ST, UK.
6
Centrum biomedicínského výzkumu, Fakultní nemocnice Hradec Králové, Sokolska 581, 50005, Hradec Kralove, Czech Republic.
7
Institut für Pharmazeutische Chemie, Goethe Universität Frankfurt, Max-von-Laue-Strasse 9, 60438, Frankfurt, Germany.
8
Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Ctra. Madrid-Barcelona, Km. 33,6, 28871, Madrid, Spain.
9
Departamento de Toxicología y Farmacología, Facultad de Veterinaria, UCM, Av. Puerta de Hierro, s/n, 28040, Madrid, Spain.
10
Universidad Camilo José Cela, C/ Castillo de Alarcón, 49, 28692, Villanueva de la Cañada, Madrid, Spain.

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.

KEYWORDS:

antioxidants; drug design; inhibitors; multitarget drugs; neurological agents

PMID:
28861918
DOI:
10.1002/anie.201706072
[Indexed for MEDLINE]

Publication type, MeSH terms, Substances

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