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Title
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Novel indolotacrine hybrids as acetylcholinesterase inhibitors: design, synthesis, biological evaluation, and molecular docking studies
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Type
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JournalPaper
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Keywords
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Indole · Tacrine · Synthesis · Molecular docking · Acetylcholinesterase inhibitors · Alzheimer’s disease
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Abstract
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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 efect 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 signifcant 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.
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Researchers
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(Not In First Six Researchers), Mohammadjavad Mahdavinejad (Not In First Six Researchers), Farshad Homayouni Moghadam (Not In First Six Researchers), Arezoo Rastegar (Not In First Six Researchers), Tahmineh Akbarzadeh (Not In First Six Researchers), Roshanak Hariri (Not In First Six Researchers), Somayeh Mojtabavi (Fifth Researcher), Mohammad Ali Faramarzi (Fourth Researcher), First-Name Last-Name (Third Researcher), ma z (Second Researcher), (First Researcher)
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