2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase.
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.
Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
Sze Wei
SW
Leong
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.
Faridah
F
Abas
Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abd. Aziz, 50300 Kuala Lumpur, Malaysia.
Kok Wai
KW
Lam
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.
Khozirah
K
Shaari
Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia. Electronic address: nordinlajis@gmail.com.
Nordin H
NH
Lajis
D000110:Acetylcholinesterase / Q000187:drug effects*; D001812:Blood-Brain Barrier; D002091:Butyrylcholinesterase / Q000187:drug effects*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D003512:Cyclohexanones / Q000737:chemistry / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D003512:Cyclohexanones; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
2-Benzoyl-6-benzylidenecyclohexanone; Acetylcholinesterase; Butyrylcholinesterase; Kinetic studies; Molecular docking