title: Synthesis, biological evaluation and molecular modeling study of novel tacrine-carbazole hybrids as potential multifunctional agents for the treatment of Alzheimer's disease.
abstract: New tacrine-carbazole hybrids were developed as potential multifunctional anti-Alzheimer agents for their cholinesterase inhibitory and radical scavenging activities. The developed compounds showed high inhibitory activity on acetylcholinesterase (AChE) with IC50 values ranging from 0.48 to 1.03 μM and exhibited good inhibition selectivity against AChE over butyrylcholinesterase (BuChE). Molecular modeling studies revealed that these tacrine-carbazole hybrids interacted simultaneously with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The derivatives containing methoxy group showed potent ABTS radical scavenging activity. Considering their neuroprotection, our results indicate that these derivatives can reduce neuronal death induced by oxidative stress and β-amyloid (Aβ). Moreover, S1, the highest potency for both radical scavenging and AChE inhibitory activity, exhibited an ability to improve both short-term and long-term memory deficit in mice induced by scopolamine. Overall, tacrine-carbazole derivatives can be considered as a candidate with potential impact for further pharmacological development in Alzheimer's therapy.
authors: Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.
authors: Supatra
authors: S
authors: Thiratmatrakul
authors: Natural Products Research Unit, Center for Innovation in Chemistry, Department of Chemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand.
authors: Chavi
authors: C
authors: Yenjai
authors: Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand.
authors: Pornthip
authors: P
authors: Waiwut
authors: Center of Excellence for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.
authors: Opa
authors: O
authors: Vajragupta
authors: Department of Chemical Technology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
authors: Prasert
authors: P
authors: Reubroycharoen
authors: Division of Medicinal Pharmacology, Institute of Natural Medicine, University of Toyama, Toyama 9300194, Japan; Wakan-yaku Theory-based Integrated Pharmacology, Graduate School of Innovative Life Science, University of Toyama,Toyama 930-0194, Japan.
authors: Michihisa
authors: M
authors: Tohda
authors: Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand. Electronic address: chaboo@kku.ac.th.
authors: Chantana
authors: C
authors: Boonyarat
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004593:Electrophorus; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy; D051379:Mice; D062105:Molecular Docking Simulation; D018384:Oxidative Stress; D013619:Tacrine / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002227:Carbazoles; D002800:Cholinesterase Inhibitors; C041514:carbazole; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Alzheimer's disease; Antioxidant; Carbazole; Cholinesterase; Molecular modeling; Tacrine