2. Academic Validation
  3. Development and Evaluation of Some Molecular Hybrids of N-(1-Benzylpiperidin-4-yl)-2-((5-phenyl-1,3,4-oxadiazol-2-yl)thio) as Multifunctional Agents to Combat Alzheimer's Disease

Development and Evaluation of Some Molecular Hybrids of N-(1-Benzylpiperidin-4-yl)-2-((5-phenyl-1,3,4-oxadiazol-2-yl)thio) as Multifunctional Agents to Combat Alzheimer's Disease

  • ACS Omega. 2023 Mar 2;8(10):9394-9414. doi: 10.1021/acsomega.2c08061.
Digambar Kumar Waiker 1,  Akash Verma 1,  Poorvi Saraf 1,  Gajendra T A 2,  Sairam Krishnamurthy 2,  Rameshwar Nath Chaurasia 3,  Sushant Kumar Shrivastava 1
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology-Banaras Hindu University, Varanasi 221005, India.
  • 2 Neurotherapeutics Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology-Banaras Hindu University, Varanasi 221005, India.
  • 3 Institute of Medical Sciences, Faculty of Medicine, Department of Neurology, Banaras Hindu University, Varanasi 221005, India.
PMID: 36936338 DOI: 10.1021/acsomega.2c08061
Abstract

A series of some novel compounds (SD-1-17) were designed following a molecular hybridization approach, synthesized, and biologically tested for hAChE, hBChE, hBACE-1, and Aβ aggregation inhibition potential to improve cognition and memory functions associated with Alzheimer's disease. Compounds SD-4 and SD-6 have shown multifunctional inhibitory profiles against hAChE, hBChE, and hBACE-1 enzymes in vitro. Compounds SD-4 and SD-6 have also shown anti-Aβ aggregation potential in self- and acetylcholinesterase (AChE)-induced thioflavin T assay. Both compounds have shown a significant propidium iodide (PI) displacement from the cholinesterase-peripheral active site (ChE-PAS) region with excellent blood-brain barrier (BBB) permeability and devoid of neurotoxic liabilities. Compound SD-6 ameliorates cognition and memory functions in scopolamine- and Aβ-induced behavioral rat models of Alzheimer's disease (AD). Ex vivo biochemical estimation revealed a significant decrease in malonaldehyde (MDA) and AChE levels, while a substantial increase of superoxide dismutase (SOD), catalase, glutathione (GSH), and ACh levels is seen in the hippocampal brain homogenates. The histopathological examination of brain slices also revealed no sign of neuronal or any tissue damage in the SD-6-treated experimental Animals. The in silico molecular docking results of compounds SD-4 and SD-6 showed their binding with hChE-catalytic anionic site (CAS), PAS, and the catalytic dyad residues of the hBACE-1 enzymes. A 100 ns molecular dynamic simulation study of both compounds with ChE and hBACE-1 enzymes also confirmed the ligand-protein complex's stability, while quikprop analysis suggested drug-like properties of the compounds.

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