N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer’s disease
As part of a project aimed at the pharmacological optimization of Contilisant, herein we describe molecular modelling studies that led to the identification of MBA-159 as a new polyfunctionalized, multitarget-directed ligand and a promising drug candidate for the treatment of Alzheimer's disease. We synthesized MBA-159 and conducted comprehensive in vitro and in vivo evaluations. In in vivo studies MBA-159 demonstrated favourable pharmacokinetics, anti-amnesic properties and significantly improved non-spatial memory (contextual and recognition memory) in a mouse model of scopolamine-induced amnesia. Additionally, MBA-159 showed a tendency to increase synaptic plasticity biomarkers and reduce neuroinflammatory trends (assessed by qPCR), as well as cognitive enhancement in a senescence-accelerated prone mouse 8 model.
Authors
- Paweł Żmudzki (ORCID: https://orcid.org/0000-0003-3594-1241)
- Ewelina Honkisz-Orzechowska
- Stanislav Gobec (ORCID: https://orcid.org/0000-0002-9678-3083)
- Anna Więckowska (ORCID: https://orcid.org/0000-0003-2549-170X)
- Damijan Knez (ORCID: https://orcid.org/0000-0001-9917-1384)
- Daniel Diez‐Iriepa (ORCID: https://orcid.org/0000-0002-8575-1246)
- Carlos Torrado‐Salmerón (ORCID: https://orcid.org/0000-0002-4123-3367)
- Isabel Iriepa (ORCID: https://orcid.org/0000-0003-3475-9624)
- Christian Griñán‐Ferré (ORCID: https://orcid.org/0000-0002-5424-9130)
- Natalia Szałaj (ORCID: https://orcid.org/0000-0003-4973-5115)
- Aina Bellver‐Sanchís (ORCID: https://orcid.org/0000-0001-9890-753X)
- Kinga Sałat (ORCID: https://orcid.org/0000-0003-0614-5393)
- Víctor Guarnizo-Herrero (ORCID: https://orcid.org/0000-0001-9323-3388)
- Francisco López‐Muñoz (ORCID: https://orcid.org/0000-0002-5188-6038)
- Paula Zaręba (ORCID: https://orcid.org/0000-0002-5037-6183)
- Óscar M. Bautista‐Aguilera (ORCID: https://orcid.org/0000-0002-1327-1681)
- Mercè Pallàs (ORCID: https://orcid.org/0000-0003-3095-4254)
- Jose Luis Marco-Contelles (ORCID: https://orcid.org/0000-0003-0690-0328)
- Marta Ribalta‐Vilella
- Borja Martínez-Alonso (ORCID: https://orcid.org/0009-0002-9124-5507)
- Guillermo Torrado Durán (ORCID: https://orcid.org/0000-0002-8865-2083)
- Aleksandra Manik
- Inaya Nsiona-Defise
Institutions
- Universidad Complutense de Madrid (ES)
- Jagiellonian University (PL)
- University of Ljubljana (SI)
- Universidad de Alcalá (ES)
- Instituto de Salud Carlos III (ES)
- HM Hospitales (ES)
- Instituto de Química Orgánica General (ES)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Biomedicine & Pharmacotherapy
- Published
- 2025-09-27
- DOI
- https://doi.org/10.1016/j.biopha.2025.118603
- Citations
- 1
- Primary Topic
- Cholinesterase and Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 1.39