Download MendeleyRapid discovery and crystallography study of highly potent and selective butylcholinesterase inhibitors based on oxime-containing libraries and conformational restriction strategies.
Jing, L., Wei, W., Meng, B., Chantegreil, F., Nachon, F., Martinez, A., Wu, G., Zhao, H., Song, Y., Kang, D., Brazzolotto, X., Zhan, P., Liu, X.(2023) Bioorg Chem 134: 106465-106465
- PubMed: 36933339
- DOI: https://doi.org/10.1016/j.bioorg.2023.106465
- Primary Citation of Related Structures:
7QHD, 7QHE - PubMed Abstract:
Butyrylcholinesterase is regarded as a promising drug target in advanced Alzheimer's disease. In order to identify highly selective and potent BuChE inhibitors, a 53-membered compound library was constructed via the oxime-based tethering approach based on microscale synthesis. Although A2Q17 and A3Q12 exhibited higher BuChE selectivity versus acetylcholinesterase, the inhibitory activities were unsatisfactory and A3Q12 did not inhibit A¦Â 1-42 peptide self-induced aggregation. With A2Q17 and A3Q12 as leads, a novel series of tacrine derivatives with nitrogen-containing heterocycles were designed based on conformation restriction strategy. The results demonstrated that 39 (IC 50 ?=?3.49?nM) and 43 (IC 50 ?=?7.44?nM) yielded much improved hBuChE inhibitory activity compared to the lead A3Q12 (IC 50 ?=?63?nM). Besides, the selectivity indexes (SI?=?AChE IC 50 / BChE IC 50 ) of 39 (SI?=?33) and 43 (SI?=?20) were also higher than A3Q12 (SI?=?14). The results of the kinetic study showed that 39 and 43 exhibited a mixed-type inhibition against eqBuChE with respective K i values of 1.715?nM and 0.781?nM. And 39 and 43 could inhibit A¦Â 1-42 peptide self-induced aggregation into fibril. X-ray crystallography structures of 39 or 43 complexes with BuChE revealed the molecular basis for their high potency. Thus, 39 and 43 are deserve for further study to develop potential drug candidates for the treatment of Alzheimer's disease.
Organizational Affiliation:
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.
