Chiral Anthranilic Amides as Potential Cholinesterase Inhibitors: Synthesis, Bioactivity Assessment, and Molecular Modeling

Abstract

Inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are central therapeutic targets for Alzheimer's disease (AD). In this study, novel chiral anthranilic amide derivatives (5a–5d, 7a, and 7b) were synthesized from chiral amines and were characterized by 1H, 13C NMR, LC–MS, and IR, then inhibitory effect of 5a–5d, 7a, and 7b on AChE/BChE activity was investigated by in vitro inhibition and in silico studies. For AChE, IC50 values of 5a–5d, 7a, and 7b were found to be 70, 63.64, 53.85, 36.84, 17.07, and 17.5 nM, respectively. For BChE, IC50 values of 5a–5d, 7a, and 7b were found as 46.66 µM, 33.33 µM, 116.6 µM, 233.3 µM, 175 nM and, 116.6 nM, respectively. All compounds had better inhibition effects against AChE than BChE. The enantioselective inhibition was observed in the compounds 5a–5d. For AChE, the S-enantiomers exhibited stronger inhibition than the R-enantiomers. However, in the case of BChE, R-enantiomers had better inhibition effects. Although molecules 7a and 7b had a stronger inhibition effect than molecules 5a–5d for AChE and BChE, the enantioselectivity was decreased in these molecules. This result was attributed to the spacer group effect in 7a and 7b.