(±)-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

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, (±)-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.

[3+2] Cycloaddition Synthesis of New Piperazine‐Linked Bis(chromene) Hybrids Possessing Pyrazole Units as Potential Acetylcholinesterase Inhibitors

“…Several reports were dedicated to examining the AChE inhibitory activity of donepezil‐analogs (see Figure 1). [4,13] These analogs were mainly designed by replacing the anti‐AChE pharmacophore, indanone unit, with a chromene unit [14,15] . Piperazine is a bio‐isosteric unit of piperidine; therefore, several reports investigated the utility of piperazine in the synthesis of promising AChE inhibitors [16,17] .…”

Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer’s Disease

“…Alzheimer’s disease (AD), the most prevalent neurodegenerative disease, is one of such multifactorial diseases that lack an effective treatment, which would greatly benefit from the development of multitarget drugs. − A key step of multitarget drug design is the selection of the targets, whose modulation should result in additive or synergistic effects, preferably on key pathogenic mechanisms …”

Ultrasound‐Mediated Synthesis of New (Piperazine‐Chromene)‐Linked Bis(thieno[2,3‐b]pyridine) Hybrids as Potential Anti‐acetylcholinesterase

“…[4,10] These analogues were constructed by substituting the pharmacophoric indanone unit for a chromene unit. [11,12] Due to the fact that piperazine is a bioisosteric unit of piperidine, several studies have looked into the use of piperazine in the synthesis of potential AChE inhibitors. [13,14] According to a recent study by Mozaffarnia et al, [15] donepezil analogues' inhibitory activity was enhanced when the piperidine part was switched out for a piperazine unit.…”

“…Numerous studies have been conducted to investigate the donepezil‐analogues′ ability to inhibit AChE (see Figure 1). [4,10] These analogues were constructed by substituting the pharmacophoric indanone unit for a chromene unit [11,12] . Due to the fact that piperazine is a bio‐isosteric unit of piperidine, several studies have looked into the use of piperazine in the synthesis of potential AChE inhibitors [13,14] .…”