Synthesis, molecular docking and biochemical analysis of aminoalkylated naphthalene-based chalcones as acetylcholinesterase inhibitors

Abstract

In this study, an efficient microwave-assisted one-step synthetic route towards Mannich base reactions was developed from 4-hydroxyacetophenone and different secondary amines in quantitative yields. The reaction was non-catalysed, reproducible on a gram scale and accomplished in a short time. Three derivatives of 2-alkyloxynaphthaldehydes were obtained from 2-hydroxynaphthaldehyde using the sonication method over a short time. All the precursors were characterised using infrared spectroscopy (IR), one-dimensional nuclear magnetic resonance spectroscopy (1D-NMR) and electron impact mass spectrometry (EIMS). Twelve novel chalcones were synthesised using thionyl chloride via Claisen-Schmidt condensation reaction between 2-alkyloxynaphthaldehydes and Mannich bases of 4-hydroxyacetophenone. The synthesised chalcones were characterised using IR, 1D- and 2D-NMR and high resolution mass spectrometry (HRMS). The selected chalcone (68) was used for crystallography analysis. X-ray single-crystal structural analysis revealed that chalcone (68) comprises three planar aromatic ring groups and a chair-shaped piperidine ring with intramolecular and intermolecular interactions. The synthesised chalcones were evaluated for their metal chelating properties using in situ ultraviolet (UV) and NMR titration studies. The presence of Mannich bases on the chalcone skeleton promotes the chelation capacity of the chalcone. The SwissADME web tool was used to assess the in silico drug-likeness properties, toxicity and pharmacokinetics of the novel chalcones. The Molinspiration server was used for target prediction, which showed the likelihood of the general scaffold of chalcone to be 93% enzyme inhibitor while the chalcones bearing the Mannich base could be a ChE inhibitor. Comparative docking analysis was carried out on all chalcone derivatives to screen their binding affinity towards the AChE enzyme (PDB 1EVE) using AutoDock4.2 and the results were visualised using BIOVIA Discovery Studio Visualizer. All the synthesised chalcones showed lower binding energy (-13.06 to -10.43 kcal/mol) against AChE, better than donepezil (-10.52 kcal/mol). All the chalcones were found active as antioxidants against 2,2-diphenyl-1-picrylhydrazyl with IC50 values that ranged between 12.57 and 55.52 µg/mL. The in vitro assessment of the chalcones inhibition activity against AChE and BuChE was carried out using the spectrophotometric method. All chalcones were potent inhibitors towards AChE, with IC50 values ranging between 0.11 and 5.34 nM more than donepezil (IC50 33.4 nM) and selectivity indexes (0.66–23.83), despite the fact that chalcones (71) and (74) were inactive. A correlation between the structure and inhibitory activity towards AChE of the synthesised chalcones was established. In short, introducing diethylamine in ring A of the chalcone skeleton and the propargyl moiety at ring B was affirmed to be a prospective drug against AChE. The multifunctional properties of chalcone (76) involving the potent AChE inhibitory activity (IC50 0.11 nM, SI 23.83) as well as its good antioxidant activity (IC50 40.58 µg/mL), low log P 3.87, and ability to permeate through the blood-brain barrier were all advantages that demonstrate it as an excellent candidate for the development of an effective drug against AChE.