Novel chalcone derivatives of ursolic acid as acetylcholinesterase inhibitors: Synthesis, characterization, biological activity, ADME prediction, molecular docking and molecular dynamics studies

Abstract

Acetylcholinesterase (AChE) is a critical target in the prevention of Alzheimer's Disease (AD) progression. With the goal of developing potential acetylcholinesterase inhibitors, a new series chalcone derivatives of ursolic acid (4–11) were synthesized and characterized by means of their NMR, FTIR and HRMS spectral data. hAChE inhibition abilities of all compounds were tested in vitro. Compounds 10, 8 and 7 showed high hAChE inhibitory potential with the IC50 values of 1.82, 4.65 and 5.36 µM respectively. When compared to the standard inhibitor (Galantamine, IC50= 1.96 µM), compound 10 was the most potent derivative. After performing kinetic studies, KM constant and Vmax value of hAChE were determined as 0.059 mM and 0.052 EU/ml respectively. Inhibition type of compound 10 was found as competitive and Ki constant was calculated as 1.31 ± 0.18 µM. The inhibition mechanism of compounds was predicted by molecular docking, MM/GBSA analysis, molecular dynamics simulation and ADME studies. Molecular docking studies showed that compounds 10, 8, and 7 have highest binding scores (-9.235, -8.827, -8.645 kcal/mol, respectively), while the standard inhibitor galantamine exhibited binding score of -5.106 kcal/mol. According to the MM/GBSA analysis, compounds 10 and 7 displayed binding free energies of -46.19 and -49.19 kcal/mol, respectively, which were higher than the standard's binding free energy of -41.82 kcal/mol. Molecular dynamic simulations were confirmed successful placement of the compounds 10, 8 and 7 in the active site of AChE. The in silico ADME predictions indicated that compound 10 has acceptable potency as a drug in treatment of AD.