2. Academic Validation
  3. Discovery of New Highly Potent Histamine H3 Receptor Antagonists, Calcium Channel Blockers, and Acetylcholinesterase Inhibitors

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

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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