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: Supatra Thiratmatrakul, Chavi Yenjai, Pornthip Waiwut, Opa Vajragupta, Prasert Reubroycharoen, Michihisa Tohda, Chantana Boonyarat
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 75 Pg. 21-30 (Mar 21 2014) ISSN: 1768-3254 [Electronic] France
• PMID: 24508831 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Antioxidants
• Carbazoles
• Cholinesterase Inhibitors
• carbazole
• Tacrine
• Acetylcholinesterase
• Butyrylcholinesterase

Topics

• Acetylcholinesterase (chemistry, metabolism)
• Alzheimer Disease (drug therapy, enzymology, metabolism)
• Amyloid beta-Peptides (metabolism)
• Animals
• Antioxidants (chemistry, pharmacology, therapeutic use)
• Butyrylcholinesterase (chemistry, metabolism)
• Carbazoles (chemistry, pharmacology, therapeutic use)
• Cell Line
• Cholinesterase Inhibitors (chemistry, pharmacology, therapeutic use)
• Electrophorus
• Humans
• Male
• Memory Disorders (chemically induced, drug therapy)
• Mice
• Molecular Docking Simulation
• Oxidative Stress
• Tacrine (chemistry, pharmacology, therapeutic use)