2. Academic Validation
  3. First Sustainable One-Pot Tandem Hantzsch Multicomponent Reaction/Click Reaction Approach for Novel Multitarget-Directed Ligands in Alzheimer's Disease

First Sustainable One-Pot Tandem Hantzsch Multicomponent Reaction/Click Reaction Approach for Novel Multitarget-Directed Ligands in Alzheimer's Disease

  • ACS Chem Neurosci. 2025 Dec 29. doi: 10.1021/acschemneuro.5c00806.
Paul J Bernard 1,  Anna Więckowska 2,  Sylvain Grosjean 1,  Justyna Godyń 2,  Kinga Sałat 3,  Jan Detka 3,  Natalia Palacz 4,  Weronika Tyrybon 4,  Jakub Jończyk 4,  Natalia Szałaj 2,  Paula Zaręba 2,  Helène Martin 5,  Maciej Maj 6,  Krzysztof Jozwiak 6,  José Marco-Contelles 7,  Lhassane Ismaili 1
Affiliations

Affiliations

  • 1 Univ. Marie et Louis Pasteur, UMR INSERM 1322 LINC, 19 rue Ambroise Paré, F-25000 Besançon, France.
  • 2 Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
  • 3 Department of Pharmacodynamics, Chair of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
  • 4 Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
  • 5 Univ. Marie et Louis Pasteur, UMR INSERM 1098 RIGHT EFS, 19 rue Ambroise Paré, F-25000 Besançon, France.
  • 6 Department of Biopharmacy, Medical University of Lublin, ul. W. Chodzki 4a, 20-093 Lublin, Poland.
  • 7 Laboratory of Medicinal Chemistry (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain.
PMID: 41460506 DOI: 10.1021/acschemneuro.5c00806
Abstract

This study explores novel multitarget-directed ligands (MTDLs) showing anticholinesterase, antioxidant, neuroprotective, and Calcium Channel inhibitory activities, as promising compounds for Alzheimer's disease (AD) treatment. The rational design combined dihydropyridines (DHPs), known for Calcium Channel blocking and neuroprotective properties, with tacrine, a cholinesterase inhibitor. The key innovation of this work lies in the one-pot tandem Hantzsch multicomponent/click reaction used to synthesize new 18 DHPs IIIa-r. This sustainable and original approach aligns with green chemistry principles by reducing waste, energy consumption, and derivatives formation. Notably, DHP IIIj and IIIk demonstrated a multitarget profile and effectively reversed scopolamine-induced amnesia in a mouse model, showcasing its antiamnesic properties. These results suggested that DHP IIIj and IIIk hold promise as innovative therapeutic candidates for AD, validating the potential of MTDL strategy and highlighting the one-pot tandem synthesis as a significant advancement in medicinal chemistry.

Keywords

Alzheimer’s disease; MTDL; click reaction; green chemistry; multicomponent reaction.

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