Contilisant-Belinostat Hybrids: Polyfunctionalized Indole Derivatives as Multineurotarget Drugs for the Potential Treatment of Alzheimer’s Disease
In this work, we designed, synthesized, and evaluated two types of multineurotargeting compounds using a pharmacophore merging strategy, aiming to develop potential treatments for Alzheimer's disease. We combined belinostat, an FDA-approved unselective histone deacetylase (HDAC) inhibitor, with the 5-substituted indole core of contilisant, known for its antioxidant and neuroprotective properties as well as its potent inhibitory activity against monoamine oxidases (MAOs), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Among these, compounds <b>8c</b> (HDAC1, IC<sub>50</sub> = 0.019 μM; HDAC6, IC<sub>50</sub> = 0.040 μM; AChE, IC<sub>50</sub> = 20.06 μM; BChE, IC<sub>50</sub> = 17.10 μM; MAO-B, IC<sub>50</sub> = 2.14 μM), and <b>9c</b> (HDAC1, IC<sub>50</sub> = 0.126 μM; HDAC6, IC<sub>50</sub> = 0.020 μM; AChE, IC<sub>50</sub> = 2.73 μM; BChE, IC<sub>50</sub> = 4.03 μM; MAO-B, IC<sub>50</sub> = 1.18 μM) emerged as the most promising candidates. These compounds warrant further investigation as potential treatments for Alzheimer's disease due to their unique inhibition profiles and favorable mode of inhibition.
Authors
- Markus Pietsch (ORCID: https://orcid.org/0000-0002-8110-2265)
- Linda Schäker‐Hübner (ORCID: https://orcid.org/0000-0001-7734-124X)
- Michael Gütschow (ORCID: https://orcid.org/0000-0002-9376-7897)
- Kathrin Tan (ORCID: https://orcid.org/0000-0003-0565-2676)
- Finn K. Hansen (ORCID: https://orcid.org/0000-0001-9765-5975)
- Gabriele Horn
- Timo Wille (ORCID: https://orcid.org/0000-0002-4359-5388)
- Paul W. Elsinghorst (ORCID: https://orcid.org/0000-0001-8999-3122)
- Sophia Eimermacher (ORCID: https://orcid.org/0000-0002-2311-3644)
- Jose Luis Marco-Contelles (ORCID: https://orcid.org/0000-0003-0690-0328)
- Vesa Krasniqi
- Alicia Porro-Pérez (ORCID: https://orcid.org/0000-0002-8310-1549)
- Mireia Toledano-Pinedo
- Philipp Stegen
Institutions
- TH Köln - University of Applied Sciences (DE)
- University of Bonn (DE)
- University of Cologne (DE)
- Universität der Bundeswehr München (DE)
- Bundeswehr Medical Service Academy (DE)
- University Hospital Cologne (DE)
- Instituto de Química Orgánica General (ES)
- Institut für Pharmakologie und Toxikologie der Bundeswehr
Publication Details
- Journal
- ACS Pharmacology & Translational Science
- Published
- 2025-02-07
- DOI
- https://doi.org/10.1021/acsptsci.4c00709
- Citations
- 4
- Primary Topic
- Histone Deacetylase Inhibitors Research
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Deutsche Forschungsgemeinschaft
- Agencia Estatal de Investigación