259731-83-4Relevant academic research and scientific papers
Synthesis, biological activity, and biopharmaceutical characterization of tacrine dimers as acetylcholinesterase inhibitors
Qian, Shuai,He, Lisi,Mak, Marvin,Han, Yifan,Ho, Chun-Yu,Zuo, Zhong
, p. 442 - 453 (2014)
Tacrine (THA), as the first approved acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD), has been extensively investigated in last seven decades. After dimerization of THA via a 7-carbon alkyl spacer, bis(7)-tacrine (B7T) showed much potent anti-AChE activity than THA. We here report synthesis, biological evaluation and biopharmaceutical characterization of six THA dimers referable to B7T. According to IC50 values, the in vitro anti-AChE activities of THA dimers were up to 300-fold more potent and 200-fold more selective than that of THA. In addition, the anti-AChE activities of THA dimers were found to be associated with the type and length of the linkage. All studied THA dimers showed much lower cytotoxicity than B7T, but like B7T, they demonstrated much lower absorptive permeabilities than that of THA on Caco-2 monolayer model. In addition, all THA dimers demonstrated significant efflux transport (efflux ratio >4), indicating that the limited permeability could be associated with the efflux transport during absorption process. Moreover, the dimer with higher Log P value was accompanied with higher permeability but lower aqueous solubility. A balanced consideration of activity, solubility, cytotoxicity and permeability should be conducted in selection of the potential candidates for further in vivo investigation.
Design, synthesis, biological evaluation, and molecular modeling studies of quinoline-ferulic acid hybrids as cholinesterase inhibitors
Mo, Jun,Yang, Hongyu,Chen, Tingkai,Li, Qihang,Lin, Hongzhi,Feng, Feng,Liu, Wenyuan,Qu, Wei,Guo, Qinglong,Chi, Heng,Chen, Yao,Sun, Haopeng
, (2019/10/05)
A series of quinoline-ferulic acid hybrids has been designed, synthesized, and evaluated as cholinesterase inhibitors. Most of the compounds showed good inhibitory activities toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, 10f was found to be the most potent inhibitor against AChE (IC50 = 0.62 ± 0.17 μM), and 14 was the most potent inhibitor against BChE (IC50 = 0.10 ± 0.01 μM). Representative compounds, such as 10f and 12g, act in a competitive manner when they inhibit AChE or BChE. Molecular docking and dynamic simulation revealed that the synthesized compounds bind to the target by simultaneously interacting with the catalytic active site (CAS) and the peripheral anionic site (PAS) of both AChE and BChE. The U-shaped confirmation was preferred when 12g bound to BChE, which was different from the linear conformation of 10f bound to AChE. Cell-based assays have confirmed the moderate neuroprotective effects of compounds 10f and 12g against H2O2-induced oxidative damage towards PC12 cells. Moreover, the hepatotoxicity of 12g was lower than that of tacrine, indicating its potential safety as an anti-Alzheimer's agent. In summary, we report a new chemotype of multifunctional hybrid, which may be further modified to develop new anti-Alzheimer's agents.
Structure-activity relationships for ferriprotoporphyrin IX association and β-hematin inhibition by 4-aminoquinolines using experimental and ab initio methods
Nsumiwa, Samkele,Kuter, David,Wittlin, Sergio,Chibale, Kelly,Egan, Timothy J.
supporting information, p. 3738 - 3748 (2013/07/19)
In order to probe structure-activity relationships of association with ferriprotoporphyrin IX (log K) and inhibition of β-hematin formation, a series of 4-aminoquinolines with varying substituents at the 7-position (X) have been synthesized. These have been further elaborated by introduction of two different R groups on the 4-amino nitrogen atom in the form of methyl (R = Me) and ethylamine (R = EtNH2) side chains. Data for a previously investigated series containing an N,N-diethyl-ethylamine side chain were also compared with the findings of this study. Experimentally, log K values for the simple 4-aminoquinoline series (R = H) were found to correlate with the hydrophobicity constant (π) of the group X. The log K values for the series with R = Me and EtNH2 were found to correlate with those of the series with R = H. The log of the 50% β-hematin inhibitory activity (log BHIA50) was found to correlate with log K and either meta (σm) or para (σp) Hammett constants for the series with R = Me and EtNH2, but not the simple series with R = H. To further improve predictability, correlations with ab initio electrostatic parameters, namely Mulliken and CHelpG charges were investigated. The best correlations were found with CHelpG charges which indicated that log K values can be predicted from the charges on atom H-8 and the group X in the quinolinium species computed in vacuum, while log BHIA50 values can be predicted from the CHelpG charges on C-7, C-8 and N-1 for the neutral species in vacuum. These correlations indicate that association and inhibition of β-hematin formation are separately determined. They also suggest that electron withdrawing groups at the 7-position, but not necessarily hydrophobic groups are required for hemozoin inhibition. The upshot is that the correlations imply that considerably more hydrophilic hemozoin inhibitors are feasible.
DIPEPTIDYL PEPTIDASE IV INHIBITOR
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Page/Page column 65, (2010/11/29)
A compound represented by general formula (I):A-B-D whereinA represents a substituted or unsubstituted 1-pyrrolidinyl group, a substituted or unsubstituted 3-thiazolidinyl group, a substituted or unsubstituted 1-oxo-3-thiazolidinyl group, or the like;B r
