Lanlan Jing, Wenxiu Wei, Bairu Meng, Fabien Chantegreil, Florian Nachon, Ana Martínez, Gaochan Wu, Huajun Zhao, Yuning Song, Dongwei Kang, Xavier Brazzolotto, Peng Zhan, Xinyong Liu, Shandong University, Shandong Province, Ministerio de Economía y Competitividad (España), Direction Générale de l'Armement (France), Jing, Lanlan, Wei, Wenxiu, Meng, Bairu, Chantegreil, Fabien, Nachon, Florian, Martínez, Ana, Wu, Gaochan, Brazzolotto, Xavier, and Liu, Xinyong
22 p.-9 fig.-8 tab., 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 Aβ1-42 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 (IC50 = 3.49 nM) and 43 (IC50 = 7.44 nM) yielded much improved hBuChE inhibitory activity compared to the lead A3Q12 (IC50 = 63 nM). Besides, the selectivity indexes (SI = AChE IC50 / BChE IC50) 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 Ki values of 1.715 nM and 0.781 nM. And 39 and 43 could inhibit Aβ1-42 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., We gratefully acknowledge financial support from the Shandong Provincial Key Research and Development Project (No. 2019JZZY021011), Science Foundation for Outstanding Young Scholars of Shandong Province (ZR2020JQ31), Foreign Cultural and Educational Experts Project (GXL20200015001), Qilu Young Scholars Program of Shandong University, Distinguished Young and Middle-aged Scholar of Shandong University, the Taishan Scholar Program at Shandong Province, and MINECO (Grants SAF2016-76693-R to A.M), F.C., F.N. and X.B. were supported by the French Ministry of Armed Forces (Direction Générale de l'Armement and Service de Santé des Armées, NBC-5-C-4210). Authors would like to thank the ESRF for long-term beamtime access (MX2329 IBS BAG).