2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase

Sze Wei Leong; Faridah Abas; Kok Wai Lam; Khozirah Shaari; Nordin H Lajis

doi:10.1016/j.bmc.2016.06.016

2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase

Bioorg Med Chem. 2016 Aug 15;24(16):3742-51. doi: 10.1016/j.bmc.2016.06.016. Epub 2016 Jun 9.

Authors

Sze Wei Leong¹, Faridah Abas², Kok Wai Lam³, Khozirah Shaari⁴, Nordin H Lajis⁵

Affiliations

¹ Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
² Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia; Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia. Electronic address: faridah_abas@upm.edu.my.
³ Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abd. Aziz, 50300 Kuala Lumpur, Malaysia.
⁴ Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia; Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
⁵ Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia. Electronic address: nordinlajis@gmail.com.

PMID: 27328658
DOI: 10.1016/j.bmc.2016.06.016

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.

Keywords: 2-Benzoyl-6-benzylidenecyclohexanone; Acetylcholinesterase; Butyrylcholinesterase; Kinetic studies; Molecular docking.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / drug effects*
Blood-Brain Barrier
Butyrylcholinesterase / drug effects*
Carbon-13 Magnetic Resonance Spectroscopy
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacokinetics
Cholinesterase Inhibitors / pharmacology*
Cyclohexanones / chemistry
Cyclohexanones / pharmacology*
Gas Chromatography-Mass Spectrometry
Humans
Inhibitory Concentration 50
Molecular Docking Simulation
Proton Magnetic Resonance Spectroscopy
Spectrometry, Mass, Electrospray Ionization
Structure-Activity Relationship

Substances

Cholinesterase Inhibitors
Cyclohexanones
Acetylcholinesterase
Butyrylcholinesterase