Acetamide Derivatives of Chromen‐2‐ones as Potent Cholinesterase Inhibitors

Abstract

Alzheimer's disease (AD), a neurodegenerative disorder, is a serious medical issue worldwide with drastic social consequences. Inhibition of cholinesterase is one of the rational and effective approaches to retard the symptoms of AD and, hence, consistent efforts are being made to develop efficient anti-cholinesterase agents. In pursuit of this, a series of 19 acetamide derivatives of chromen-2-ones were synthesized and evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential. All the synthesized compounds exhibited significant anti-AChE and anti-BChE activity, with IC values in the range of 0.24-10.19 μM and 0.64-30.08 μM, respectively, using donepezil hydrochloride as the standard. Out of 19 compounds screened, 3 compounds, viz. 22, 40, and 43, caused 50% inhibition of AChE at 0.24, 0.25, and 0.25 μM, respectively. A kinetic study revealed them to be mixed-type inhibitors, binding with both the CAS and PAS sites of AChE. The above-selected compounds were found to be effective inhibitors of AChE-induced and self-mediated Aβ aggregation. ADMET predictions demonstrated that these compounds may possess suitable blood-brain barrier (BBB) permeability. Hemolytic assay results revealed that these compounds did not lyse human RBCs up to a thousand times of their IC value. MTT assays performed for the shortlisted compounds showed them to be negligibly toxic after 24 h of treatment with the SH-SY5Y neuroblastoma cells. These results provide insights for further optimization of the scaffolds for designing the next generation of compounds as lead cholinesterase inhibitors.

DNA-binding and Kinetics AChE Inhibition studies of Cobalt(II) and Copper(II) Complexes Derived from 5-[4-(dimethylamino) phenyl]-3-(2-oxo-2H-chromen-3-yl)-1H-pyrazole-1-carbothioamide

“…The progress of reactions completion was indicated by TLC technique after determination the purification in ethyl acetate: hexane eluent chromatogram. The table (1) represents the main characterization of the chalcone, ligand and its complexes through measurements of elemental analyses, melting points, colors and their percent yields. However the elemental analysis data for the chalcone, and the free pyrazoline ligand are consistent with their chemical formula C21H18N4O2S.…”

“…A mixtures (1.282 m moles) of ethonolic solution of ligand and metal chlorides (1.282 m moles (0.217) CuCl2.2H2O),(0.349 g, CoCl2.6H2O),and (0.36 gm of ZnCl2) with (1 mmole, 0.433g gm) of ligand dissolved in (15 ml) of hot ethanol were refluxed for (three) hrs, then add drops of 5% NH4OH solution to maintain the pH to≈6-7). The precipitate was filtered off, dried in vacuum desiccator, Table (1).…”

“…The H NMR spectrum of derivative chalcone in d6-DMSO solvent, Figure (1) showed singlet peak at 3.77 ppm assigning to the nuclear spin of up-field aliphatic -CH3 protons attached to N-atom to 6H protons. The de shielded protons of -CH=CHwere observed as singlet and doublet peaks around (8.80-9.80) ppm respectively.…”

“…During the last few decades, considerable progress has been made in the field of anticancer chemistry, although tumor resistance to drugs and other side effects of drug administration are crucial problems in this field [1,2]. To address these problems, researchers are designing new chemotherapeutic agents based on transition metal ions.…”