Discovery of New Highly Potent Histamine H3 Receptor Antagonists, Calcium Channel Blockers, and Acetylcholinesterase Inhibitors

  • ACS Chem Neurosci. 2024 Sep 18;15(18):3363-3383. doi: 10.1021/acschemneuro.4c00341.
Rim Malek  1  2 ,  Kinga Sałat  3 ,  Perle Totoson  4 ,  Tadeusz Karcz  5 ,  Bernard Refouvelet  1 ,  Anna Skrzypczak-Wiercioch  6 ,  Maciej Maj  7 ,  Alexey Simakov  4 ,  Helene Martin  4 ,  Agata Siwek  8 ,  Natalia Szałaj  9 ,  Justyna Godyń  9 ,  Dawid Panek  9 ,  Anna Więckowska  9 ,  Krzysztof Jozwiak  7 ,  Celine Demougeot  4 ,  Katarzyna Kieć-Kononowicz  5 ,  Fakher Chabchoub  2 ,  Isabel Iriepa  10  11 ,  José Marco-Contelles  12  13 ,  Lhassane Ismaili  1
Affiliations
  • 1. Université de Franche-Comté, INSERM, UMR 1322 LINC, F-25000 Besançon, France.
  • 2. Laboratory of Applied Chemistry: Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax, University of Sfax, B. P 802, Sfax 3000, Tunisia.
  • 3. Department of Pharmacodynamics, Chair of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków 30-688, Poland.
  • 4. Université de Franche-Comté, EFS, INSERM, UMR 1098 RIGHT, F-25000 Besançon, France.
  • 5. Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
  • 6. University Centre of Veterinary Medicine JU-UA, University of Agriculture in Krakow, 24/28 Mickiewicz St., Kraków 30-059, Poland.
  • 7. Department of Biopharmacy, Medical University of Lublin, ul. W. Chodzki 4a, Lublin 20-093, Poland.
  • 8. Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
  • 9. Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
  • 10. Universidad de Alcalá. Departamento de Química Orgánica y Química Inorgánica, Alcalá de Henares, Madrid 28805, Spain.
  • 11. Instituto de Investigación Química Andrés M. del Río (IQAR), Universidad de Alcalá, Alcalá de Henares, Madrid 28805, Spain, Grupo DISCOBAC, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM).
  • 12. Laboratory of Medicinal Chemistry (IQOG, CSIC), C/ Juan de la Cierva 3, Madrid 28006, Spain.
  • 13. CIBER, ISCIII, Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid 28006, Spain.
PMID: 39208251 DOI: 10.1021/acschemneuro.4c00341
Abstract

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 3e 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 H3 receptors, and blocking voltage-gated calcium channels. Additionally, compound 3e exhibited remarkable neuroprotective activity against H2O2 and Aβ1-40, 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.

Keywords
Alzheimer’s disease; Biginelli reaction; calcium channels; cholinesterase; histamine H3 receptor; neuroprotection.
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