Skip to content

Research at St Andrews

Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine H3R antagonism for neurodegenerative diseases

Research output: Contribution to journalArticle

DOI

Author(s)

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 & 1 others Holger Stark

School/Research organisations

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.
Close

Details

Original languageEnglish
Article number201706072R2
Pages (from-to)12765–12769
Number of pages5
JournalAngewandte Chemie International Edition
Volume56
Issue number41
Early online date1 Sep 2017
DOIs
StatePublished - 2 Oct 2017

    Research areas

  • Antioxidants, Drug design, Inhibitors, Multitarget drugs, Neurological agents

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Assessment of enzyme inhibition: a review with examples from the development of monoamine oxidase and cholinesterase inhibitory drugs

    Ramsay, R. R. & Tipton, K. F. Jul 2017 In : Molecules. 22, 7, 46 p., 1192

    Research output: Contribution to journalReview article

  2. Comparative analysis of the neurochemical profile and MAO inhibition properties of N-(furan-2-ylmethyl)-N-methylprop-2-yn-1-amine

    De Deurwaerdère, P., Binda, C., Corne, R., Leone, C., Valeri, A., Valoti, M., Ramsay, R. R., Fall, Y. & Marco-Contelles, J. 17 May 2017 In : ACS Chemical Neuroscience. 8, 5, p. 1026-1035 10 p., cn-2016-00377h

    Research output: Contribution to journalArticle

  3. Neurobiology and neuropharmacology of monoaminergic systems

    Deurwaerdère, P., Ramsay, R. R. & Di Giovanni, G. Apr 2017 In : Progress in Neurobiology. 151, p. 1-3 3 p., PRONEU 1480

    Research output: Contribution to journalEditorial

  4. Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer’s disease treatment

    Hroch, L., Guest, P., Benek, O., Soukup, O., Janockova, J., Dolezal, R., Kuca, K., Aitken, L., Smith, T. K., Gunn-Moore, F., Zala, D., Ramsay, R. R. & Musilek, K. 1 Feb 2017 In : Bioorganic & Medicinal Chemistry. 25, 3, p. 1143-1152 10 p.

    Research output: Contribution to journalArticle

  5. Editorial: Structure-based drug design for diagnosis and treatment of neurological diseases

    Ramsay, R. R. & Di Giovanni, G. 24 Jan 2017 In : Frontiers in Pharmacology. 8, 1 p., 13

    Research output: Contribution to journalEditorial

Related by journal

  1. Pac13 is a small, monomeric dehydratase that mediates the formation of the 3′-deoxy nucleoside of pacidamycins

    Michailidou, F., Chung, C., Brown, M. J. B., Bent, A. F., Naismith, J. H., Leavens, W. J., Lynn, S. M., Sharma, S. V. & Goss, R. J. M. 30 Aug 2017 In : Angewandte Chemie International Edition. Early View

    Research output: Contribution to journalArticle

  2. Aryloxide-facilitated catalyst turnover in enantioselective α,β-unsaturated acyl ammonium catalysis

    Matviitsuk, A., Greenhalgh, M., Barrios Antunez, D., Slawin, A. & Smith, A. D. 25 Aug 2017 In : Angewandte Chemie International Edition. Early View

    Research output: Contribution to journalArticle

  3. Synthesis, characterization, and computational analysis of the dialanate dianion, [H3Al-AlH3]2−: a valence isoelectronic analogue of ethane

    Bonyhady, S. J., Holzmann, N., Frenking, G., Stasch, A. & Jones, C. 10 Jul 2017 In : Angewandte Chemie International Edition. 56, 29, p. 8527-8531 5 p.

    Research output: Contribution to journalArticle

  4. Hyperconjugation is the source of helicity in perfluorinated n-alkanes

    Cormanich, R. A., O'Hagan, D. & Buehl, M. 26 Jun 2017 In : Angewandte Chemie International Edition. 129, 27, p. 7975-7978 4 p.

    Research output: Contribution to journalArticle

ID: 251083893