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  2. Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer's disease

Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer's disease

  • Eur J Med Chem. 2020 Jul 15;198:112257. doi: 10.1016/j.ejmech.2020.112257.
Yash Pal Singh 1 Gullanki Naga Venkata Charan Tej 1 Amruta Pandey 1 Khushbu Priya 2 Pankaj Pandey 3 Gauri Shankar 1 Prasanta Kumar Nayak 1 Geeta Rai 2 Amar G Chittiboyina 3 Robert J Doerksen 4 Swati Vishwakarma 1 Gyan Modi 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India.
  • 2 Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
  • 3 National Center for Natural Products Research, University of Mississippi, University, MS, 38677, United States.
  • 4 Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS, 38677, United States.
  • 5 Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India. Electronic address: gpmodi.phe@itbhu.ac.in.
Abstract

In our overall goal to overcome the limitations associated with Natural Products for the management of Alzheimer's disease and to develop in-vivo active multifunctional cholinergic inhibitors, we embarked on the development of ferulic acid analogs. A systematic SAR study to improve upon the cholinesterase inhibition of ferulic acid with analogs that also had lower logP was carried out. Enzyme inhibition and kinetic studies identified compound 7a as a lead molecule with preferential acetylcholinesterase inhibition (AChE IC50 = 5.74 ± 0.13 μM; BChE IC50 = 14.05 ± 0.10 μM) compared to the parent molecule ferulic acid (% inhibition of AChE and BChE at 20 μM, 15.19 ± 0.59 and 19.73 ± 0.91, respectively). Molecular docking and dynamics studies revealed that 7a fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Asp74, Trp286, and Tyr337 in AChE and with Tyr128, Trp231, Leu286, Ala328, Phe329, and Tyr341 in BChE. Compound 7a was found to be an efficacious antioxidant in a DPPH assay (IC50 = 57.35 ± 0.27 μM), and it also was able to chelate iron. Data from atomic force microscopy images demonstrated that 7a was able to modulate aggregation of amyloid β1-42. Upon oral administration, 7a exhibited promising in-vivo activity in the scopolamine-induced AD animal model and was able to improve spatial memory in cognitive deficit mice in the Y-maze model. Analog 7a could effectively reverse the increased levels of AChE and BChE in scopolamine-treated Animals and exhibited potent ex-vivo antioxidant properties. These findings suggest that 7a can act as a lead molecule for the development of naturally-inspired multifunctional molecules for the management of Alzheimer's and other neurodegenerative disorders.

Keywords

Acetylcholinesterase; Alzheimer’s disease; Amyloid-beta; Antioxidant; Docking; Ferulic acid; Multifunctional targeted ligands.

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