Synthesis, biological evaluation and molecular modeling study of novel tacrine–carbazole hybrids as potential multifunctional agents for the treatment of Alzheimer's disease

• Published in: European journal of medicinal chemistry Vol. 75; pp. 21 - 30
• Main Authors: Thiratmatrakul, Supatra, Yenjai, Chavi, Waiwut, Pornthip, Vajragupta, Opa, Reubroycharoen, Prasert, Tohda, Michihisa, Boonyarat, Chantana
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 21.03.2014; Elsevier
• Subjects: Acetylcholinesterase - chemistry; Acetylcholinesterase - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - enzymology; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; Antioxidant; Antioxidants - chemistry; Antioxidants - pharmacology; Antioxidants - therapeutic use; Butyrylcholinesterase - chemistry; Butyrylcholinesterase - metabolism; Carbazole; Carbazoles - chemistry; Carbazoles - pharmacology; Carbazoles - therapeutic use; Cell Line; Chemistry, Medicinal; Cholinesterase; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Cholinesterase Inhibitors - therapeutic use; Electrophorus; Humans; Life Sciences & Biomedicine; Male; Memory Disorders - chemically induced; Memory Disorders - drug therapy; Mice; Molecular Docking Simulation; Molecular modeling; Oxidative Stress; Pharmacology & Pharmacy; Science & Technology; Tacrine; Tacrine - chemistry; Tacrine - pharmacology; Tacrine - therapeutic use; AChE; AD; PAS; Antioxidant; MTT; Carbazole; Cholinesterase; Aβ; CAS; BuChE; Molecular modeling; AChEI; MAO; Alzheimer's disease; Tacrine; ABTS; TARGET-DIRECTED LIGANDS; MELATONIN; PEPTIDE; BETA-AMYLOID AGGREGATION; ACETYLCHOLINESTERASE; MEMORY; DRUGS; DUAL INHIBITORS; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.01.020

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. [Display omitted] •Tacrine–carbazole hybrids were developed as multifunctional anti-Alzheimer agents.•Tacrine–carbazole hybrids exhibited antioxidant activity better than trolox.•Tacrine–carbazole hybrids showed high inhibition selectivity against AChE over BuChE.•Tacrine–carbazole hybrids interact simultaneously with the CAS and PAS of AChE.•S1 exhibited an ability to improve memory deficit in mice induced by scopolamine.