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2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2016 Aug 15; Vol. 24 (16), pp. 3742-51. Date of Electronic Publication: 2016 Jun 09. - Publication Year :
- 2016
-
Abstract
- In the present study, a series of 2-benzoyl-6-benzylidenecyclohexanone analogs have been synthesized and evaluated for their anti-cholinesterase activity. Among the forty-one analogs, four compounds (38, 39, 40 and 41) have been identified as lead compounds due to their highest inhibition on both AChE and BChE activities. Compounds 39 and 40 in particular exhibited highest inhibition on both AChE and BChE with IC50 values of 1.6μM and 0.6μM, respectively. Further structure-activity relationship study suggested that presence of a long-chain heterocyclic in one of the rings played a critical role in the dual enzymes' inhibition. The Lineweaver-Burk plots and docking results suggest that both compounds could simultaneously bind to the PAS and CAS regions of the enzyme. ADMET analysis further confirmed the therapeutic potential of both compounds based upon their high BBB-penetrating. Thus, 2-benzoyl-6-benzylidenecyclohexanone containing long-chain heterocyclic amine analogs represent a new class of cholinesterase inhibitor, which deserve further investigation for their development into therapeutic agents for cognitive diseases such as Alzheimer.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Subjects :
- Blood-Brain Barrier
Carbon-13 Magnetic Resonance Spectroscopy
Cholinesterase Inhibitors chemistry
Cholinesterase Inhibitors pharmacokinetics
Cyclohexanones chemistry
Gas Chromatography-Mass Spectrometry
Humans
Inhibitory Concentration 50
Molecular Docking Simulation
Proton Magnetic Resonance Spectroscopy
Spectrometry, Mass, Electrospray Ionization
Structure-Activity Relationship
Acetylcholinesterase drug effects
Butyrylcholinesterase drug effects
Cholinesterase Inhibitors pharmacology
Cyclohexanones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 24
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 27328658
- Full Text :
- https://doi.org/10.1016/j.bmc.2016.06.016