title: Biological evaluation of synthetic α,β-unsaturated carbonyl based cyclohexanone derivatives as neuroprotective novel inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation.
abstract: A series of new α,β-unsaturated carbonyl-based cyclohexanone derivatives was synthesized by simple condensation method and all compounds were characterized by using various spectroscopic techniques. New compounds were evaluated for their effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds were also screened for in vitro cytotoxicity and for inhibitory activity for self-induced Aβ1-42 aggregation. The effect of these compounds against amyloid β-induced cytotoxicity was also investigated. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against AChE and self-induced Aβ1-42 aggregation. The compound 3o exhibited best AChE (IC50=0.037μM) inhibitory potential. Furthermore, compound 3o disassembled the Aβ fibrils produced by self-induced Aβ aggregation by 76.6%. Compounds containing N-methyl-4-piperidone linker, showed high acetylcholinesterase and self-induced Aβ aggregation inhibitory activities as compared to reference drug donepezil. The pre-treatment of cells with synthetic compounds protected them against Aβ-induced cell death by up to 92%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment and our study suggest the cyclohexanone derivatives as promising new inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases.
authors.affiliation: Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan 430070, PR China.
authors.forename: Gao-Feng
authors.initials: GF
authors.lastname: Zha
authors.affiliation: Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan 430070, PR China.
authors.forename: Cheng-Pan
authors.initials: CP
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan 430070, PR China. Electronic address: qinhuali@whut.edu.cn.
authors.forename: Hua-Li
authors.initials: HL
authors.lastname: Qin
authors.affiliation: Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Jantan
authors.affiliation: Department of Chemistry, University of Sargodha, Sargodha 40100, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Sher
authors.affiliation: Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
authors.forename: Muhammad Wahab
authors.initials: MW
authors.lastname: Amjad
authors.affiliation: Department of Chemistry, University of Sargodha, Sargodha 40100, Pakistan.
authors.forename: Muhammad Ajaz
authors.initials: MA
authors.lastname: Hussain
authors.affiliation: Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam Campus, Bandar Puncak Alam 42300, Selangor, Malaysia.
authors.forename: Zahid
authors.initials: Z
authors.lastname: Hussain
authors.affiliation: Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia. Electronic address: snab@ukm.edu.my.
authors.forename: Syed Nasir Abbas
authors.initials: SN
authors.lastname: Bukhari
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D003512:Cyclohexanones / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066329:Protein Aggregates / Q000187:drug effects; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D003512:Cyclohexanones; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Alzheimer’s disease; Dementia; Neurodegeneration; Neuroprotection