Design, Synthesis and Biological Assessment of Novel 2‐(4‐Alkoxybenzylidine)‐2,3‐dihydro‐5,6‐dimethoxy‐1H‐inden‐1‐one Derivatives as hAChE and hBuChE Enzyme Inhibitors

Abstract

A novel series of 2‐(4‐alkoxybenzylidine)‐2,3‐dihydro‐5,6‐dimethoxy‐1H‐inden‐1‐one derivatives were designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBuChE) enzymes. The in vitro studies showed that some of these molecules exhibited a significant ability to inhibit AChE and BuChE. Among them, 2‐[4‐[2‐(piperidine‐1‐yl)ethoxy]benzylidine]‐2,3‐dihydro‐5,6‐dimethoxy‐1H‐inden‐1‐one exhibited the most potent inhibitory activity with IC50 values of 0.3 and 7.4 μM for AChE and BuChE, respectively. This compound was found to be less toxic than donepezil.

Bioactive Aurones, Indanones, and Other Hemiindigoid Scaffolds: Medicinal Chemistry and Photopharmacology Perspectives

“…Similarly, swapping to an indanone scaffold did not cause a significant change in the inhibition potency. As an illustration, compound 72 , which resembles to a reverse indanone-based 70 , gave nearly identical AChE inhibition values (IC 50 = 0.3 μM) . However, shortening the linker between the B-ring and the piperidine moiety resulted in the production of aurone 73 , with a far better AChE inhibition efficacy (IC 50 = 8.8 nM against eeAChE, 37 nM against the human enzyme), a remarkable exception among several other amino analogues which provided little or no improvement of the previously described activities .…”

“…As an illustration, compound 72, which resembles to a reverse indanone-based 70, gave nearly identical AChE inhibition values (IC 50 = 0.3 μM). 102 However, shortening the linker between the B-ring and the piperidine moiety resulted in the production of aurone 73, with a far better AChE inhibition efficacy (IC 50 = 8.8 nM against eeAChE, 37 nM against the human enzyme), a remarkable exception among several other amino analogues which provided little or no improvement of the previously described activities. 103 Another series of 4′-substituted indanones was first reported in 2016, bearing this time amino groups directly bound to the B-ring.…”

Mode of binding, kinetic and thermodynamic properties of a lipid-like drug (Fingolimod) interacting with Human Serum Albumin

“… 4 , 26 , 39 The chemical structure of Fingolimod was drawn with ChemBioDraw software and energy-optimized using Chembioultra MM2 and AM1 methods. 40 , 41 Polar hydrogens and Kollman charges were added to the HSA structure before modeling. Also, water molecules were removed.…”

In Silico, in Vitro and in Vivo Investigation of a Newly Synthesized Ionic Compound As Anti-Alzheimer Multi-Target Dual AChE/BuChE Inhibitor Possessing Neuro-Protective Effects Against Aβ Induced Neurotoxicity in PC12 Cells and Alzheimer Rat Model

“…Some researchers introduced a number of derivatives with permanently charged quaternary ammonium moieties substituted in para position of the benzene and investigated the probable improvement of dual-site inhibition of hAChE and hBuChE [31], improving water solubility [32] and at the same time to increase the choline transporter binding capability and consequent potential delivery by improving the steric surrounding of the cationic nitrogen [27]. Some piperazenium derivatives and evaluate their biological activities against AD in our recent paper [33], 25 . Two newly designed derivatives, including quaternary ammonium substitution ( gure 2) along with other derivatives from our previous paper [34], [35] were investigated for their dual AChE/BuChE inhibition activity.…”