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Synthesis, biological evaluation and molecular modeling study of novel tacrine-carbazole hybrids as potential multifunctional agents for the treatment of Alzheimer's disease.
Eur J Med Chem. 2014 Mar 21; 75:21-30.EJ

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+Show Affiliations

Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.Natural Products Research Unit, Center for Innovation in Chemistry, Department of Chemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand.Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand.Center of Excellence for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.Department of Chemical Technology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.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.Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand. Electronic address: chaboo@kku.ac.th.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24508831

Citation

Thiratmatrakul, Supatra, et al. "Synthesis, Biological Evaluation and Molecular Modeling Study of Novel Tacrine-carbazole Hybrids as Potential Multifunctional Agents for the Treatment of Alzheimer's Disease." European Journal of Medicinal Chemistry, vol. 75, 2014, pp. 21-30.
Thiratmatrakul S, Yenjai C, Waiwut P, et al. Synthesis, biological evaluation and molecular modeling study of novel tacrine-carbazole hybrids as potential multifunctional agents for the treatment of Alzheimer's disease. Eur J Med Chem. 2014;75:21-30.
Thiratmatrakul, S., Yenjai, C., Waiwut, P., Vajragupta, O., Reubroycharoen, P., Tohda, M., & Boonyarat, C. (2014). Synthesis, biological evaluation and molecular modeling study of novel tacrine-carbazole hybrids as potential multifunctional agents for the treatment of Alzheimer's disease. European Journal of Medicinal Chemistry, 75, 21-30. https://doi.org/10.1016/j.ejmech.2014.01.020
Thiratmatrakul S, et al. Synthesis, Biological Evaluation and Molecular Modeling Study of Novel Tacrine-carbazole Hybrids as Potential Multifunctional Agents for the Treatment of Alzheimer's Disease. Eur J Med Chem. 2014 Mar 21;75:21-30. PubMed PMID: 24508831.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis, biological evaluation and molecular modeling study of novel tacrine-carbazole hybrids as potential multifunctional agents for the treatment of Alzheimer's disease. AU - Thiratmatrakul,Supatra, AU - Yenjai,Chavi, AU - Waiwut,Pornthip, AU - Vajragupta,Opa, AU - Reubroycharoen,Prasert, AU - Tohda,Michihisa, AU - Boonyarat,Chantana, Y1 - 2014/01/22/ PY - 2013/08/02/received PY - 2013/10/16/revised PY - 2014/01/11/accepted PY - 2014/2/11/entrez PY - 2014/2/11/pubmed PY - 2014/10/28/medline KW - Alzheimer's disease KW - Antioxidant KW - Carbazole KW - Cholinesterase KW - Molecular modeling KW - Tacrine SP - 21 EP - 30 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 75 N2 - 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. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/24508831/Synthesis_biological_evaluation_and_molecular_modeling_study_of_novel_tacrine_carbazole_hybrids_as_potential_multifunctional_agents_for_the_treatment_of_Alzheimer's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(14)00051-8 DB - PRIME DP - Unbound Medicine ER -