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Cinnamoyl-N-Acylhydrazone-Donepezil Hybrids: Synthesis and Evaluation of Novel Multifunctional Ligands Against Neurodegenerative Diseases
- Source :
- Neurochemical Research. 45:3003-3020
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- A new series of ten multifunctional Cinnamoyl-N-acylhydrazone-donepezil hybrids was synthesized and evaluated as multifunctional ligands against neurodegenerative diseases. The molecular hybridization approach was based on the combination of 1-benzyl-4-piperidine fragment from the anti-Alzheimer AChE inhibitor donepezil (1) and the cinnamoyl subunit from curcumin (2), a natural product with remarkable antioxidant, neuroprotective and anti-inflammatory properties, using a N-acylhydrazone fragment as a spacer subunit. Compounds 4a and 4d showed moderate inhibitory activity towards AChE with IC50 values of 13.04 and 9.1 µM, respectively. In addition, compound 4a and 4d showed a similar predicted binding mode to that observed for donepezil in the molecular docking studies. On the other hand, compounds 4a and 4c exhibited significant radical scavenging activity, showing the best effects on the DPPH test and also exhibited a significant protective neuronal cell viability exposed to t-BuOOH and against 6-OHDA insult to prevent the oxidative stress in Parkinson’s disease. Similarly, compound 4c was capable to prevent the ROS formation, with indirect antioxidant activity increasing intracellular GSH levels and the ability to counteract the neurotoxicity induced by both OAβ1-42 and 3-NP. In addition, ADMET in silico prediction indicated that both compounds 4a and 4c did not show relevant toxic effects. Due to their above-mentioned biological properties, compounds 4a and 4c could be explored as lead compounds in search of more effective and low toxic small molecules with multiple neuroprotective effects for neurodegenerative diseases.
- Subjects :
- 0301 basic medicine
Multifunctional ligand
Antioxidant
DPPH
medicine.medical_treatment
Ligands
medicine.disease_cause
Biochemistry
Neuroprotection
Molecular hybridization
Structure-Activity Relationship
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
0302 clinical medicine
Cell Line, Tumor
medicine
Humans
Donepezil
Viability assay
Natural product
Molecular Structure
Chemistry
Hydrazones
Neurotoxicity
Neurodegenerative Diseases
Free Radical Scavengers
General Medicine
medicine.disease
Cinnamoyl-N-acylhydrazone-donepezil hybrids MTDL
Molecular Docking Simulation
Neuroprotective Agents
030104 developmental biology
Cinnamates
Butyrylcholinesterase
Acetylcholinesterase
Curcumin
Cholinesterase Inhibitors
030217 neurology & neurosurgery
Oxidative stress
Protein Binding
Subjects
Details
- ISSN :
- 15736903 and 03643190
- Volume :
- 45
- Database :
- OpenAIRE
- Journal :
- Neurochemical Research
- Accession number :
- edsair.doi.dedup.....315a821c440ab6178238d08df7f33a67