Exploring Novel Quinoline-1,3,4-Oxadiazole Derivatives for Alzheimer’s Disease: Their Design, Synthesis, and In-Vitro and In-Silico Investigations

Abstract

Introduction: Alzheimer’s Disease (AD) is a complicated and advanced neurodegenerative condition accompanied by gradual cholinergic neuronal death and higher levels of monoamine oxidase-B (MAO-B) enzyme. In this study, a series of novel hybrid compounds combining 1,3,4-oxadiazole and quinoline moieties were synthesized and evaluated for their potential as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and MAO enzymes. Methods: The chemical structures of the synthesized compounds were confirmed using various analytical techniques, such as mass spectrometry, infrared spectroscopy (IR), proton nuclear magnetic resonance (1H-NMR), and carbon and nuclear magnetic resonance (13C-NMR). The final products were evaluated for anticholinesterase potential by applying modified Ellman’s spectrometric method, whereas a fluorometric method was used to assess MAO inhibition properties. In-silico studies using molecular docking and molecular dynamics simulation (MDS) methods has been also conducted. Results: Among the synthesized compounds, 5a, 5c, and 6a demonstrated substantial activity against AChE, with IC50 values of 0.033 μM, 0.096 μM, and 0.177 μM, respectively. A molecular docking study was performed to elucidate the binding modes and establish the structure-activity relationship (SAR) of the most active compounds (5a, 5c, and 6a). Molecular dynamics simulation (MDS) of the most potent compound, 5a, was also conducted to examine the stability of the interactions with the receptor. Moreover, the physicochemical properties of the active products were also studied. Conclusion: Overall, this research contributes to the development of 1,3,4-oxadiazole- quinoline hybrids as potential AChE inhibitors for the treatment of Alzheimer’s disease.