Author:
Yu Dehong,Yang Can,Liu Yi,Lu Tao,Li Lizi,Chen Gang,Liu Zerong,Li Yanfang
Abstract
AbstractAlzheimer’s disease (AD) is the most common type of age-related dementia. Inhibition of butyrylcholinesterase (BChE) emerge as an effective therapeutic target for AD. A series of new substituted acetamide derivatives were designed, synthesized and evaluated for their ability to inhibit BChE. The bioassay results revealed that several compounds displayed attractive inhibition against BChE). Among them, compound 8c exhibited the highest BChE inhibition with IC50 values of 3.94 μM. Lineweaver Burk plot indicated that 8c acted as a mixed-type BChE inhibitor. In addition, docking studies confirmed the results obtained through in vitro experiments, and showed that 8c bound to the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE active site. Meanwhile, its ADME parameters were approximated using in silico method. Molecular dynamics simulation studies on the complex of 8c-BChE were performed, RMSD, RMSF, Rg, SASA, and the number of hydrogen bonds were calculated as well. These results implied that 8c could serve as appropriate lead molecule for the development of BChE inhibitor.
Funder
The Open Project of Central Nervous System Drug Key Laboratory of Sichuan Province
Publisher
Springer Science and Business Media LLC
Reference31 articles.
1. Gauthier, S., Webster, C., Servaes, S., Morais, J. A. & Rosa-Neto, P. World Alzheimer report 2022: Life after diagnosis: Navigating treatment, care and support (2022).
2. Francis, P. T., Palmer, A. M., Snape, M. & Wilcock, G. K. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J. Neurol. Neurosurg. Psychiatry. 66, 137–147 (1999).
3. Jouanne, M., Rault, S. & Voisin-Chiret, A. S. Tau protein aggregation in Alzheimer’s disease: an attractive target for the development of novel therapeutic agents. Eur. J. Med. Chem. 139, 153–167 (2017).
4. Jomov, K., Vondrakova, D., Lawson, M. & Valko, M. Metals, oxidative stress and neurodegenerative disorders. Mol. Cell. Biochem. 345, 91–104 (2010).
5. McHardy, S. F., Wang, H. L., McCowen, S. V. & Valdez, M. C. Recent advances in acetylcholinesterase Inhibitors and Reactivators: an update on the patent literature (2012–2015). Expert Opin. Ther. Pat. 27(4), 455–476 (2017).
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