(±)-BIGI-3h: Pentatarget-Directed Ligand combining Cholinesterase, Monoamine Oxidase, and Glycogen Synthase Kinase 3β Inhibition with Calcium Channel Antagonism and Antiaggregating Properties for Alzheimer’s Disease

• Published in: ACS chemical neuroscience Vol. 12; no. 8; pp. 1328 - 1342
• Main Authors: Ismaili, Lhassane, Monnin, Julie, Etievant, Adeline, Arribas, Raquel L, Viejo, Lucía, Refouvelet, Bernard, Soukup, Ondrej, Janockova, Jana, Hepnarova, Vendula, Korabecny, Jan, Kucera, Tomas, Jun, Daniel, Andrys, Rudolf, Musilek, Kamil, Baguet, Aurelie, García-Frutos, Eva M, De Simone, Angela, Andrisano, Vincenza, Bartolini, Manuela, de los Ríos, Cristóbal, Marco-Contelles, José, Haffen, Emmanuel
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 21-04-2021; American Chemical Society (ACS)
• Subjects: Life Sciences; Neurobiology; Neurons and Cognition; calcium channel; MAO; Biginelli reaction; Alzheimer’s disease; GSK 3β; cholinesterases
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.0c00803

Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer’s disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3β and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±)-BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and β-amyloid peptide. The in vivo studies have shown that (±)-BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits.