Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer’s Disease Therapy

Abstract

In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer’s disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 µM), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.

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

“…Electronic supplementary information (ESI): General experimental procedures, m.p., spectral data ( 1 H-, 13 C-NMR and IR) and elemental analyses of the synthesized compounds; Copies of…”

“… [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] . 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.…”

“…-and13 C-NMR of the synthesized compounds; Detailed assays for anti-AChE and DPPH free radicals inhibitory activity.…”

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

“… [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] . Mozaffarnia et al.…”

“…[14,15] Piperazine is a bioisosteric unit of piperidine; therefore, several reports investigated the utility of piperazine in the synthesis of promising AChE inhibitors. [16,17] Mozaffarnia et al recently reported that replacing the piperidine part with a piperazine unit improved the inhibitory activity of donepezil-analogs. [18] Furthermore, the promising AChE inhibitory activity of pyrazole-based scaffolds has been investigated in numerous reports.…”