55727-53-2Relevant academic research and scientific papers
Dual targeting of acetylcholinesterase and tau aggregation: Design, synthesis and evaluation of multifunctional deoxyvasicinone analogues for Alzheimer's disease
Manzoor, Shoaib,Gabr, Moustafa T.,Rasool, Bisma,Pal, Kavita,Hoda, Nasimul
, (2021/09/28)
Development of multitargeted ligands have demonstrated remarkable efficiency as potential therapeutics for Alzheimer's disease (AD). Herein, we reported a new series of deoxyvasicinone analogues as dual inhibitor of acetylcholinesterase (AChE) and tau aggregation that function as multitargeted ligands for AD. All the multitargeted ligands 11(a-j) and 15(a-g) were designed, synthesized, and validated by 1HNMR, 13CNMR and mass spectrometry. All the synthesized compounds 11(a-j) and 15(a-g) were screened for their ability to inhibit AChE, BACE1, amyloid fibrillation, α-syn aggregation, and tau aggregation. All the screened compounds possessed weak inhibition of BACE-1, Aβ42 and α-syn aggregation. However, several compounds were identified as potential hits in the AChE inhibitory screening assay and cellular tau aggregation screening. Among all compounds, 11f remarkably inhibited AChE activity and cellular tau oligomerization at single-dose screening (10 μM). Moreover, 11f displayed a half-maximal inhibitory concentration (IC50) value of 0.91 ± 0.05 μM and half-maximal effective concentration (EC50) value of 3.83 ± 0.51 μM for the inhibition of AChE and cellular tau oligomerization, respectively. In addition, the neuroprotective effect of 11f was determined in tau-expressing SH-SY5Y cells incubated with Aβ oligomers. These findings highlighted the potential of 11f to function as a multifunctional ligand for the development of promising anti-AD drugs.
Novel hydroxybenzylamine-deoxyvasicinone hybrids as anticholinesterase therapeutics for Alzheimer's disease
Ayyadevara, Srinivas,Balasubramaniam, Meenakshisundaram,Bowroju, Suresh K.,Crooks, Peter A.,Lakkaniga, Naga Rajiv,Penthala, Narsimha R.,Shmookler Reis, Robert J.
, (2021/07/28)
A series of novel 2-hydroxybenzylamine-deoxyvasicinone hybrid analogs (8a-8n) have been synthesized and evaluated as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and as inhibitors of amyloid peptide (Aβ1-42) aggregation, for treatment of Alzheimer's disease (AD). These dual acting compounds exhibited good AChE inhibitory activities ranging from 0.34 to 6.35 μM. Analogs 8g and 8n were found to be the most potent AChE inhibitors in the series with IC50 values of 0.38 μM and 0.34 μM, respectively. All the analogs (8a-8n) exhibited weak BuChE inhibitory activities ranging from 14.60 to 21.65 μM. Analogs 8g and 8n exhibited BuChE with IC50 values of 15.38 μM and 14.60 μM, respectively, demonstrating that these analogs were greater than 40-fold more selective for inhibition of AChE over BuChE. Additionally, compounds 8g and 8n were also found to be the best inhibitors of self-induced Aβ1-42 peptide aggregation with IC50 values of 3.91 μM and 3.22 μM, respectively; 8g and 8n also inhibited AChE-induced Aβ1-42 peptide aggregation by 68.7% and 72.6%, respectively. Kinetic analysis and molecular docking studies indicate that analogs 8g and 8n bind to a new allosteric pocket (site B) on AChE. In addition, the observed inhibition of AChE-induced Aβ1-42 peptide aggregation by 8n is likely due to allosteric inhibition of the binding of this peptide at the CAS site on AChE. Overall, these results indicate that 8g and 8n are examples of dual-acting lead compounds for the development of highly effective anti-AD drugs.
Novel Deoxyvasicinone-Donepezil Hybrids as Potential Multitarget Drug Candidates for Alzheimer's Disease
Du, Hongtao,Liu, Xinlian,Xie, Jusen,Ma, Fang
, p. 2397 - 2407 (2019/03/07)
In this study, we designed and synthesized a series of deoxyvasicinone-donepezil hybrids and determined whether they could be used as novel multitarget inhibitors for Alzheimer's disease. In vitro studies showed that most of the hybrids demonstrated moderate to potent inhibition of hAChE, BACE1, and Aβ1-42 aggregation. In particular, the hybrids 10a, 10d, 11a, and 11j exhibited excellent inhibitory activities against hAChE (IC50 = 56.14, 5.91, 3.29, and 8.65 nM, respectively), BACE1 (IC50 = 0.834, 0.167, 0.129, and 0.085 μM, respectively), and Aβ1-42 aggregation (IC50 = 13.26, 19.43, 9.26, and 5.41 μM, respectively). In addition, 10a and 11a exhibited very low cytotoxicity and showed remarkable neuroprotective activity against Aβ1-42-induced damage in SH-SY5Y cells.
Novel deoxyvasicinone derivatives as potent multitarget-directed ligands for the treatment of Alzheimer's disease: Design, synthesis, and biological evaluation
Ma, Fang,Du, Hongtao
, p. 118 - 127 (2017/09/20)
A series of multitarget ligands was designed by introducing several structurally diverse aminoacetamide groups at position 6 of the deoxyvasicinone group, with the aim of obtaining novel multifunctional anti-Alzheimer's disease agents using deoxyvasicinone as the substrate. In vitro studies showed that almost all of the derivatives were potent inhibitors of human recombinant acetylcholinesterase (hAChE) and human serum butyrylcholinesterase (hBChE), with IC50 values in the low nanomolar range, and exhibited moderate to high inhibition of Aβ1?42 self-aggregation. In particular, compounds 12h, 12n, and 12q showed promising inhibitory activity for hAChE, with IC50 values of 5.31 ± 2.8, 4.09 ± 0.23, and 7.61 ± 0.53 nM, respectively. Compounds 12h and 12q also exhibited the greatest ability to inhibit hBChE, with IC50 values of 4.35 ± 0.32 and 2.35 ± 0.14 nM, respectively. Moreover, enzyme kinetics confirmed that compound 12q caused a mixed type of AChE inhibition, by binding to both the active sites (PAS and CAS) of AChE. Remarkably, compound 12q also demonstrated the highest potential inhibitory activity for Aβ1?42 self-aggregation (63.9 ± 4.9%, 10 μM), and it was also an excellent metal chelator.
Directions of reactions of 6-amino-, -acetylamino-, and- benzoylaminodeoxyvasicinones with aldehydes
Elmuradov,Abdurazakov,Shakhidoyatov
experimental part, p. 262 - 267 (2010/09/18)
6-Acetylamino- and -benzoylamino-9-arylidenedeoxyvasicinones were synthesized by reaction of 6-amino-(3), -acetylamino- (4), and -benzoylamino- (5) -deoxyvasicinones (DOV) with aromatic aldehydes and furfurol in glacial acetic acid. It was shown that the amino group of 6-aminodeoxyvasicinone underwent acylation upon reaction with aldehydes to form 6-acetylamino-DOV, which reacted with aldehydes to form 9-arylidene derivatives. Carrying out this condensation in toluene, o-xylene, and ethanol produced a mixture of condensation products at the 6-amino- and α-CH2-groups. It was found that condensati on of 3 with 4-nitrobenzaldehyde in pyridine formed exclusively the Schiff bases. Methods for preparing 6-nitrodeoxyvasicinone and for its reduction were improved.
