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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 T4, 5 ; Hariri R4 ; Rastegari A5 ; Homayouni Moghadam F6 ; Mahdavi M7 ; Najafi Z8
Authors

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.
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