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Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer’s Agents: Design, Synthesis and Biological Evaluation
- Source :
- Molecules; Volume 22; Issue 6; Pages: 1006, Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry
- Publication Year :
- 2017
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2017.
-
Abstract
- A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer’s agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybrid K1383, bearing two methylene tether between two basic scaffolds, was found to be very potent hAChE inhibitor (IC50 = 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC50 ≥ 500 μM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed on hAChE with the most active compound in the study, K1383, pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies.
- Subjects :
- 6-chlorotacrine
enzyme inhibitor
Pharmaceutical Science
Glucuronates
01 natural sciences
Article
Analytical Chemistry
Structure-Activity Relationship
chemistry.chemical_compound
Alzheimer Disease
Drug Discovery
medicine
Humans
Apigenin
Physical and Theoretical Chemistry
IC50
Butyrylcholinesterase
Scutellarin
biology
010405 organic chemistry
Organic Chemistry
Biological activity
acetylcholinesterase
scutellarin
Acetylcholinesterase
0104 chemical sciences
Enzyme Activation
Molecular Docking Simulation
010404 medicinal & biomolecular chemistry
chemistry
Biochemistry
Blood-Brain Barrier
Chemistry (miscellaneous)
Docking (molecular)
Enzyme inhibitor
Drug Design
Tacrine
biology.protein
Molecular Medicine
Cholinesterase Inhibitors
Alzheimer’s disease
butyrylcholinesterase
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 14203049
- Database :
- OpenAIRE
- Journal :
- Molecules; Volume 22; Issue 6; Pages: 1006
- Accession number :
- edsair.doi.dedup.....a1c24a48e5a1f4b71c3f9867db3a767c
- Full Text :
- https://doi.org/10.3390/molecules22061006