Synthesis, in vitro analysis and molecular docking study of novel benzoxazole-based oxazole derivatives for the treatment of Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is treated by targeting cholinesterase enzymes like acetylcholinesterase and butyrylcholinesterase, and these enzymes' inhibitors serve as important tools for treatment of alzheimer diseases. Hybrid analogues with a 1,3-oxazole moiety based on benzoxazole were designed, developed, and then tested for their cholinesterase inhibition. All the newly synthesized analogues showed moderate to good inhibitory potentials having IC50 values raging between 0.90 ± 0.05 µM to 35.20 ± 0.70 µM against acetylcholinesterase and 1.10 ± 0.10 µM to 37.70 ± 0.60 µM against butyrylcholinesterase enzymes. Among the series, the analogue 11 (IC50 = 0.90 ± 0.05 µM), (IC50 = 1.10 ± 0.10 µM) and 18 (IC50 = 1.20 ± 0.05 µM), (IC50 = 2.10 ± 0.10 µM) being the strongest acetylcholinesterase and butyrylcholinesterase inhibitors as compared to standard donepezil drug. Nonetheless, the remaining analogues also displayed better inhibition profile against both these targeted enzymes. Furthermore, the structures of all the synthesized analogues were confirmed by using HREI-MS, 1HNMR and 13CNMR spectroscopy. Additionally, molecular docking experiments were conducted to determine the potential mode of interaction between the majority of active analogues and the enzyme active site. The findings corroborated the experimental data.