Biginelli Reaction Synthesis of Novel Multitarget-Directed Ligands with Ca2+ Channel Blocking Ability, Cholinesterase Inhibition, Antioxidant Capacity, and Nrf2 Activation

Rim Malek; Alexey Simakov; Audrey Davis; Maciej Maj; Paul J Bernard; Artur Wnorowski; Helene Martin; José Marco-Contelles; Fakher Chabchoub; Patrick Dallemagne; Christophe Rochais; Krzysztof Jozwiak; Lhassane Ismaili

doi:10.3390/molecules28010071

Biginelli Reaction Synthesis of Novel Multitarget-Directed Ligands with Ca²⁺ Channel Blocking Ability, Cholinesterase Inhibition, Antioxidant Capacity, and Nrf2 Activation

Molecules. 2022 Dec 22;28(1):71. doi: 10.3390/molecules28010071.

Authors

Affiliations

¹ Laboratoire LINC UR 481, Pôle de Chimie Médicinale, University Franche-Comté, UFR Santé, 19, rue Ambroise Paré, F-25000 Besançon, France.
² Laboratory of Applied Chemistry: Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax, University of Sfax, Sfax 3000, Tunisia.
³ PEPITE EA4267, University Franche-Comté, F-25000 Besançon, France.
⁴ Centre d'Etudes et de Recherche sur le Médicament de Normandie, Normandie University, Unicaen, CERMN, 14000 Caen, France.
⁵ Department of Biopharmacy, Medical University of Lublin, ul. W. Chodzki 4a, 20-093 Lublin, Poland.
⁶ Laboratory of Medicinal Chemistry (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain.

Abstract

Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software.

Keywords: Biginelli reaction; Nrf2; calcium channel antagonism; multitarget-directed ligands.

MeSH terms

Alzheimer Disease* / drug therapy
Antioxidants* / chemical synthesis
Calcium Channel Blockers* / chemical synthesis
Cholinesterase Inhibitors* / chemical synthesis
Humans
Ligands
Molecular Targeted Therapy*
NF-E2-Related Factor 2* / metabolism
Structure-Activity Relationship

Substances

Antioxidants
Cholinesterase Inhibitors
Ligands
NF-E2-Related Factor 2
Calcium Channel Blockers

Grants and funding

This work was supported by the Regional Council of Franche-Comté (2022Y-13659 and 13660 ACCURATE PROJECT) and CERMN (Centre d’Etudes et de Recherche sur le Médicament de Normandie).