jm2c00944_si_003.pdb (660.47 kB)
N‑Benzyl Benzamide Derivatives as Selective Sub-Nanomolar Butyrylcholinesterase Inhibitors for Possible Treatment in Advanced Alzheimer’s Disease
datasetposted on 2022-08-15, 15:00 authored by Chenxi Du, Lei Wang, Qianwen Guan, Hongyu Yang, Tingkai Chen, Yijun Liu, Qihang Li, Weiping Lyu, Xin Lu, Ying Chen, Yang Liu, Hui Liu, Feng Feng, Wenyuan Liu, Zongliang Liu, Wei Li, Yao Chen, Haopeng Sun
Herein, we report a series of selective sub-nanomolar inhibitors against butyrylcholinesterase (BChE). These compounds, bearing a novel N-benzyl benzamide scaffold, inhibited BChE with IC50 from picomolar to nanomolar. The inhibitory activity was confirmed by the surface plasmon resonance assay, showing a sub-nanomolar KD value, which revealed that the compounds exert the inhibitory effect through directly binding to BChE. Several compounds showed neuroprotective effects verified by the oxidative damage model. Furthermore, the safety of S11-1014 and S11-1033 was demonstrated by the in vivo acute toxicity test. In the behavior study, 0.5 mg/kg S11-1014 or S11-1033 exhibited a marked therapeutic effect, which was almost equal to the treatment with 1 mg/kg rivastigmine, against the cognitive impairment induced by Aβ1–42. The pharmacokinetics studies characterized the metabolic stability of S11-1014. Thus, N-benzyl benzamide inhibitors are promising compounds with drug-like properties for improving cognitive dysfunction, providing a potential strategy for the treatment of Alzheimer’s disease.
pharmacokinetics studies characterizedoxidative damage modelimproving cognitive dysfunctioncognitive impairment inducedmarked therapeutic effectadvanced alzheimer ’1033 b1014 b50 subnanomolar butyrylcholinesterase inhibitorsalzheimer ’nanomolar inhibitorsn k inhibitory effect subselective subpotential strategymetabolic stabilitylike propertiesinhibitory activitydirectly bindingbehavior studyalmost equal>< sub5 mg1 mg