838816-25-4Relevant academic research and scientific papers
Claulansine F-donepezil hybrids as anti-alzheimer’s disease agents with cholinergic, free-radical scavenging, and neuroprotective activities
Chen, Xinyi,Li, Chuangjun,Liu, Ke,Ma, Jie,Wang, Weiping,Wang, Xiaoliang,Yang, Jingzhi,Zang, Yingda,Zhang, Dongming
, (2021/05/31)
The multifactorial nature of Alzheimer’s disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A total of 26 Claulansine F-donepezil hybrids were designed and synthesized as multitarget drugs. Among these compounds, six compounds exhibited excellent acetylcholinesterase (AChE) inhibitory activity (half maximal inhibitory concentration (IC50) 1.63-4.62 μM). Moreover, (E)-3-(8-(tert-Butyl)-3,3-dimethyl-3,11-dihydropyrano[3,2-a]carbazol- 5-yl)-N-((1-(2-chlorobenzyl)piperidin-4-yl)methyl)acrylamide (6bd) exhibited better neuroprotective effects against OGD/R (oxygen-glucose deprivation/reoxygenation) than lead compound Claulansine F. Furthermore, 6bd could cross the blood-brain barrier in vitro. More importantly, compared to edaravone, 6bd had stronger free-radical scavenging activity. Molecular docking studies revealed that 6bd could interact with the catalytic active site of AChE. All of these outstanding in vitro results indicate 6bd as a leading structure worthy of further investigation.
Design, synthesis, in vitro and in vivo evaluation of benzylpiperidine-linked 1,3-dimethylbenzimidazolinones as cholinesterase inhibitors against Alzheimer’s disease
Mo, Jun,Chen, Tingkai,Yang, Hongyu,Guo, Yan,Li, Qi,Qiao, Yuting,Lin, Hongzhi,Feng, Feng,Liu, Wenyuan,Chen, Yao,Liu, Zongliang,Sun, Haopeng
, p. 330 - 343 (2019/12/30)
Cholinesterase inhibitor plays an important role in the treatment of patients with Alzheimer’s disease (AD). Herein, we report the medicinal chemistry efforts leading to a new series of 1,3-dimethylbenzimidazolinone derivatives. Among the synthesised compounds, 15b and 15j showed submicromolar IC50 values (15b, eeAChE IC50 = 0.39 ± 0.11 μM; 15j, eqBChE IC50 = 0.16 ± 0.04 μM) towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Kinetic and molecular modelling studies revealed that 15b and 15j act in a competitive manner. 15b and 15j showed neuroprotective effect against H2O2-induced oxidative damage on PC12 cells. This effect was further supported by their antioxidant activity determined in a DPPH assay in vitro. Morris water maze test confirmed the memory amelioration effect of the two compounds in a scopolamine-induced mouse model. Moreover, the hepatotoxicity of 15b and 15j was lower than tacrine. In summary, these data suggest 15b and 15j are promising multifunctional agents against AD.
Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists
Adlere,Sun,Zarca,Roumen,Gozelle,Viciano Perpi?á,Caspar,Arimont,Bebelman,Briddon,Hoffmann,Hill,Smit,Vischer,Wijtmans,de Graaf,de Esch,Leurs
, p. 631 - 649 (2018/11/27)
Using the available structural information of the chemokine receptor CXCR4, we present hit finding and hit exploration studies that make use of virtual fragment screening, design, synthesis and structure-activity relationship (SAR) studies. Fragment 2 was identified as virtual screening hit and used as a starting point for the exploration of 31 N-substituted piperidin-4-yl-methanamine derivatives to investigate and improve the interactions with the CXCR4 binding site. Additionally, subtle structural ligand changes lead to distinct interactions with CXCR4 resulting in a full to partial displacement of CXCL12 binding and competitive and/or non-competitive antagonism. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and binding model studies were used to identify important hydrophobic interactions that determine binding affinity and indicate key ligand-receptor interactions.
