Discovery of new acetylcholinesterase inhibitors derived from quinazolinones: synthesis, in vitro, and molecular docking study

In the present study, twelve quinazolinones ( 2, 3, 4a–4j ) were successfully synthesized. Among them, five compounds ( 4c, 4d, 4f, 4h, 4i ) were newly reported. Furthermore, twelve compounds were assessed against acetylcholinesterase (AChE). Seven compounds ( 4b, 4c, 4d, 4f, 4g, 4h, 4j ) showed inhibitory activity above 70%, where compounds 4c and 4h had inhibitory activity with IC₅₀ values of 2.97 and 5.86 μM, respectively. The kinetic study showed that compounds 4c and 4h exhibited mixed-type inhibition. Molecular docking suggested that compounds 4c and 4h displayed binding energy values of −8.7 and −8.4 kcal/mol. Compound 4c showed H-bonds with four residues (Tyr124, Tyr337, Tyr341, and Glu202), but compound 4h formed H-bonds with three residues (Tyr124, Tyr133, and Glu202) in the binding pocket of AChE. Thus, quinazolinone derivatives with a nitro group at the C-6 and alkoxy groups at the C-7 position have the potential for further investigation as AChE inhibitors.