Synthesis and evaluation of coumarin/piperazine hybrids as acetylcholinesterase inhibitors
- 56 Downloads
A series of new coumarin/piperazine hybrids were synthesized and evaluated for anticholinesterase activity. Among them, compounds 4d and 4t exhibited potent human acetylcholinesterase (hAChE) inhibitory activity with IC50 values of 2.42 and 9.89 μM, respectively, and 4t displayed highest selectivity toward hAChE over human butyrylcholinesterase (hBChE) by 9.8-fold. In addition, both compounds did not show observed cytotoxicity against SH-SY5Y neuroblastoma cell line at 100 μM. Kinetic analysis in tandem with molecular docking study revealed that these hybrids targeted both catalytic active site (CAS) and peripheral anionic site (PAS) of hAChE. The preliminary results highlighted 4t as an anti-Alzheimer’s disease lead compound worthy of further investigation.
KeywordsCoumarin/piperazine hybrid Acetylcholinesterase inhibitor Molecular docking Cytotoxicity Alzheimer’s disease
This research work was financially supported by the Natural Science Foundation of China (No. 21672082) and Shandong Key Development Project (No. 2016GSF201209).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Barreiro EJ, Camara CA, Verli H, Brazil-Más L, Castro NG, Cintra WM, Aracava Y, Rodrigues CR, Fraga CA (2003) Design, synthesis, and pharmacological profile of novel fused pyrazolo[4,3-d]pyridine and pyrazolo[3,4-b][1,8]naphthyridine isosteres: a new class of potent and selective acetylcholinesterase inhibitors. J Med Chem 46:1144–1152CrossRefPubMedGoogle Scholar
- Demir Özkay Ü, Can ÖD, Sağlık BN, Turan N (2017) A benzothiazole/piperazine derivative with acetylcholinesterase inhibitory activity: Improvement in streptozotocin-induced cognitive deficits in rats Pharmacol Rep 69:1349–1356Google Scholar
- Girisha HR, Narendra Sharath Chandra JN, Boppana S, Malviya M, Sadashiva CT, Rangappa KS (2009) Active site directed docking studies: synthesis and pharmacological evaluation of cis-2,6-dimethyl piperidine sulfonamides as inhibitors of acetylcholinesterase. Eur J Med Chem 44:4057–4062CrossRefPubMedGoogle Scholar
- Nachon F, Carletti E, Ronco C, trovaslet M, Nicolet Y, Jean L, Renard P (2013) Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer’s drugs targeting acetyl and butyrylcholinesterase. Biochem J 453:393–399CrossRefPubMedGoogle Scholar
- Więckowska A, Więckowski K, Bajda M, Brus B, Sałat K, Czerwińska P, Gobec S, Filipek B, Malawska B (2015) Synthesis of new N-benzylpiperidine derivatives as cholinesterase inhibitors with β-amyloid anti-aggregation properties and beneficial effects on memory in vivo. Bioorg Med Chem 23:2445–2457CrossRefPubMedGoogle Scholar