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Some promising acetylcholinesterase (AChE) inhibitors with an antioxidant potential were designed, synthesised, and evaluated for their role in treating cognitive dysfunctions. The in silico Gaussian-based quantitative structureactivity relationship (QSAR), virtual screening (VS), QikProp drug-likeliness prediction and docking pose filtration protocols were adapted to design and screen the novel series of diaryl ether derivatives. Further, the selected compounds were investigated for their molecular binding stability using molecular dynamics (MD) simulation analysis and molecular mechanics generalised born surface area (MM-GBSA). The identified hits were synthesised and evaluated for their in vitro AChE inhibition and antioxidant potential. Among all the synthesized compounds, the compound 39 was observed as potent AChE inhibitor (AChE IC50 = 1.30 ± 0.09 μm; Ki = 0.054 ± 0.009 μM), and also the antioxidant potential of compound 39 (52.9%) was observed significantly better than standard donepezil (<10%) and parallel to ascorbic acid (56.6%). Further, compound 39 ameliorated the scopolamine-induced cognitive impairment in the Y-maze and passive avoidance testsin mice models. Ex vivo and biochemical analysis established the brain AChE inhibitory potential and antioxidant properties of compound 39. The results signified compound 39 to be a promising lead for the treatment of cognitive dysfunctions. [ABSTRACT FROM AUTHOR]

Ferulic acid-based multifunctional molecular hybrids of 1,3,4-oxadiazoles were designed, synthesized, and biologically evaluated for the treatment of Alzheimer's disease. Among the synthesized compounds, the derivatives with 4- hydroxy-3,5-dimethoxy substituent (FA5 and CFA5) showed balanced inhibitory potential against hAChE, hBChE, and hBACE-1. Also, CFA5displayed remarkable PAS-AChE binding with significant displacement of propidium iodide, and appreciable blood-brain barrier permeability predictions in PAMPA-BBB assay. The thioflavin T assay in self- and AChE-induced experiments established the considerable anti-Aâ aggregatory activity of CFA5. Compound CFA5 also showed neuroprotective activity in Aâ-induced oxidative stress against SH-SY5Y neuroblastoma cell lines. Moreover, in vivo behavioral studies showed amelioration of cognitive dysfunction in rats tested by Y-maze. In silico molecular docking study showed consensual binding interactions of CFA5 with active binding site residues of AChE and BACE-1. [ABSTRACT FROM AUTHOR]