Design and Development of Multifunctional Hybrids of Ferulic Acid and 1,3,4-Oxadiazoles for the Treatment of Alzheimer’s Disease

Order of Publishing in Issue: 
9
Volume :14
Issue :1
January, 2020 - March, 2020
Page No: 
81-96
Authors: 
Avanish Tripathi#, Priyanka Kumari Choubey#, Ankit Seth, Piyoosh Sharma, Manish Kumar Tripathi and Sushant Kumar Shrivastava*
Address: 
Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India

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.

Keywords: 
Alzheimer’s disease, Acetylcholinesterase (AChE), â-secretase-1 (BACE-1), Aâ aggregation, Molecular hybridization, Multifunctional agents.
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