Discovery of New Highly Potent Histamine H<sub>3</sub> Receptor Antagonists, Calcium Channel Blockers, and Acetylcholinesterase Inhibitors
At present, one of the most promising strategies to tackle the complex challenges posed by Alzheimer's disease (AD) involves the development of novel multitarget-directed ligands (MTDLs). To this end, we designed and synthesized nine new MTDLs using a straightforward and cost-efficient one-pot Biginelli three-component reaction. Among these newly developed compounds, one particular small molecule, named <b>3e</b> has emerged as a promising MTDL. This compound effectively targets critical biological factors associated with AD, including the simultaneous inhibition of cholinesterases (ChEs), selective antagonism of H<sub>3</sub> receptors, and blocking voltage-gated calcium channels. Additionally, compound <b>3e</b> exhibited remarkable neuroprotective activity against H<sub>2</sub>O<sub>2</sub> and Aβ<sub>1-40</sub>, and effectively restored cognitive function in AD mice treated with scopolamine in the novel object recognition task, confirming that this compound could provide a novel and innovative therapeutic approach for the effective treatment of AD.
Authors
- R.S. Malek (ORCID: https://orcid.org/0000-0002-8555-5683)
- Céline Demougeot (ORCID: https://orcid.org/0000-0003-0639-9756)
- Dawid Panek (ORCID: https://orcid.org/0000-0002-3211-7188)
- Anna Więckowska (ORCID: https://orcid.org/0000-0003-2549-170X)
- Lhassane Ismaïli (ORCID: https://orcid.org/0000-0002-6013-3150)
- Justyna Godyń (ORCID: https://orcid.org/0000-0002-0295-2772)
- Agata Siwek (ORCID: https://orcid.org/0000-0001-5321-9266)
- Isabel Iriepa (ORCID: https://orcid.org/0000-0003-3475-9624)
- Perle Totoson
- Tadeusz P. Karcz (ORCID: https://orcid.org/0000-0003-4035-659X)
- Maciej Maj (ORCID: https://orcid.org/0000-0002-3435-2544)
- Natalia Szałaj (ORCID: https://orcid.org/0000-0003-4973-5115)
- Alexey Simakov (ORCID: https://orcid.org/0000-0002-3076-0030)
- Kinga Sałat (ORCID: https://orcid.org/0000-0003-0614-5393)
- Katarzyna Kieć‐Kononowicz (ORCID: https://orcid.org/0000-0002-6752-7443)
- Bernard Refouvelet (ORCID: https://orcid.org/0000-0002-7939-1600)
- Hélène Martin (ORCID: https://orcid.org/0000-0001-8318-3858)
- Jose Luis Marco-Contelles (ORCID: https://orcid.org/0000-0003-0690-0328)
- Fakher Chabchoub (ORCID: https://orcid.org/0000-0003-4375-0277)
- Anna Skrzypczak-Wiercioch (ORCID: https://orcid.org/0000-0003-3057-4278)
- Krzysztof Jóźwiak (ORCID: https://orcid.org/0000-0001-6018-5092)
Institutions
- Medical University of Lublin (PL)
- Jagiellonian University (PL)
- University of Sfax (TN)
- Inserm (FR)
- Universidad de Alcalá (ES)
- Instituto de Salud Carlos III (ES)
- University of Agriculture in Krakow (PL)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Instituto de Química Orgánica General (ES)
- Université de Franche-Comté (FR)
Publication Details
- Journal
- ACS Chemical Neuroscience
- Published
- 2024-08-29
- DOI
- https://doi.org/10.1021/acschemneuro.4c00341
- Citations
- 3
- Primary Topic
- Phenothiazines and Benzothiazines Synthesis and Activities
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- Ministère de l'Europe et des Affaires Étrangères
- Ministry of Higher Education and Scientific Research
- Conseil régional de Bourgogne-Franche-Comté