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

Abstract

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, (±)<b>-BIGI-3h</b> was identified as a promising new hit compound showing <i>in vitro</i> balanced activities toward the aforementioned recognized AD targets. Additional <i>in vitro</i> studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and β-amyloid peptide. The <i>in vivo</i> studies have shown that (±)<b>-BIGI-3h</b> (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits.