Novel Indolotacrine Hybrids As Acetylcholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies

Novel Indolotacrine Hybrids As Acetylcholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies Publisher

Babaee S¹ ; Zolfigol MA¹ ; Chehardoli G² ; Faramarzi MA³ ; Mojtabavi S³ ; Akbarzadeh T^{4, 5} ; Hariri R⁴ ; Rastegari A⁵ ; Homayouni Moghadam F⁶ ; Mahdavi M⁷ ; Najafi Z⁸

Show Affiliations

1. Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
2. Department of Medicinal Chemistry, School of Pharmacy, Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
3. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
4. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
5. Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran
6. Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
7. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
8. Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran

Source: Journal of the Iranian Chemical Society Published:2023

Abstract

A new class of indolotacrine hybrids including cyclopenta- and cyclohexa-indolotacrine derivatives was designed, synthesized, and assessed as acetylcholinesterase inhibitors (AChEIs). Some of the designed derivatives indicated a good inhibitory effect against acetylcholinesterase (AChE). Among them, cyclopenta-indolotacrine hybrids showed a slightly better anti-AChE activity than cyclohexa-indolotacrine hybrids. Compound 5-amino-4-(4-chlorophenyl)-2-(1H-indol-3-yl)-4,6,7,8-tetrahydrocyclopenta[b]pyrano[3,2-e]pyridine-3-carbonitrile (8g) including 4-chlorophenyl and cyclopentane ring showed the best AChE inhibitory activity with IC50 value of 0.4 µM. The kinetic study indicated that compound 8g acted as a competitive inhibitor. Based on molecular docking results, it occupied both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE. Using a neuroprotective assay against H2O2-induced cell death in PC12 neurons, only compound 8b with 4-methoxyphenyl moiety and cyclopentane ring illustrated significant protection (P < 0.0001) at a concentration of 100 μM compared to quercetin at a concentration of 10 μM (P < 0.0001). In silico ADME studies estimated good drug-likeness for the designed compounds. As a result, these indolotacrine hybrids can be a very encouraging AChE inhibitor to treat Alzheimer’s disease. © 2023, Iranian Chemical Society.

Style	Citing Format
MLA	Babaee S, et al.. "Novel Indolotacrine Hybrids As Acetylcholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies." Journal of the Iranian Chemical Society, vol. 20, no. 5, 2023, pp. 1049-1060.
APA	Babaee S, Zolfigol MA, Chehardoli G, Faramarzi MA, Mojtabavi S, Akbarzadeh T, Hariri R, Rastegari A, Homayouni Moghadam F, Mahdavi M, Najafi Z (2023). Novel Indolotacrine Hybrids As Acetylcholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies. Journal of the Iranian Chemical Society, 20(5), 1049-1060.
Chicago	Babaee S, Zolfigol MA, Chehardoli G, Faramarzi MA, Mojtabavi S, Akbarzadeh T, Hariri R, et al.. "Novel Indolotacrine Hybrids As Acetylcholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies." Journal of the Iranian Chemical Society 20, no. 5 (2023): 1049-1060.
Harvard	Babaee S et al. (2023) 'Novel Indolotacrine Hybrids As Acetylcholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies', Journal of the Iranian Chemical Society, 20(5), pp. 1049-1060.
Vancouver	Babaee S, Zolfigol MA, Chehardoli G, Faramarzi MA, Mojtabavi S, Akbarzadeh T, et al.. Novel Indolotacrine Hybrids As Acetylcholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies. Journal of the Iranian Chemical Society. 2023;20(5):1049-1060.
BibTex	@article{ author = {Babaee S and Zolfigol MA and Chehardoli G and Faramarzi MA and Mojtabavi S and Akbarzadeh T and Hariri R and Rastegari A and Homayouni Moghadam F and Mahdavi M and Najafi Z}, title = {Novel Indolotacrine Hybrids As Acetylcholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies}, journal = {Journal of the Iranian Chemical Society}, volume = {20}, number = {5}, pages = {1049-1060}, year = {2023} }
RIS	TY - JOUR AU - Babaee S AU - Zolfigol MA AU - Chehardoli G AU - Faramarzi MA AU - Mojtabavi S AU - Akbarzadeh T AU - Hariri R AU - Rastegari A AU - Homayouni Moghadam F AU - Mahdavi M AU - Najafi Z TI - Novel Indolotacrine Hybrids As Acetylcholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies JO - Journal of the Iranian Chemical Society VL - 20 IS - 5 SP - 1049 EP - 1060 PY - 2023 ER -

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