New coumarin-benzotriazole based hybrid molecules as inhibitors of acetylcholinesterase and amyloid aggregation

Singh, Atamjit; Sharma, Sahil; Arora, Saroj; Attri, Shivani; Kaur, Prabhjot; Gulati, Harmandeep Kaur; Bhagat, Kavita; Kumar, Nitish; Singh, Harbinder; Singh, Jatinder; Bedi, Preet Mohinder Singh

doi:10.1016/j.bmcl.2020.127477

Cited by 53 publications

(29 citation statements)

References 40 publications

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“…These concentration conditions were used to overcome solubility problems of some compounds in the aqueous phosphate buffer working medium. Compounds 4c and 4d are very weakly effective in the inhibition of amyloid self- and Cu(II)-induced aggregation, but all the other compounds ( 4a , 4b , 5a , 5b and 5d ) present average/good inhibition capacity regarding Aβ 42 self-aggregation (39.0–58.7%) These compounds are more potent inhibitors than tacrine (28.1%), though weaker than curcumin (65.7%), a selected reference compound, as an anti-amyloidogenic agent with a 62% Aβ inhibition at 50 μM concentration reported [ 61 ]. Moreover, the inhibition of Cu(II)-induced Aβ 42 aggregation by compounds 4a , 4b , 5a , 5b and 5d is also moderate/good (41.2–60.8%), with values only slightly higher than those obtained for self-aggregation inhibition, suggesting that no substantial effect can be observed due to the presence of Cu(II).…”

Section: Resultsmentioning

confidence: 99%

Novel Rivastigmine Derivatives as Promising Multi-Target Compounds for Potential Treatment of Alzheimer’s Disease

et al. 2022

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Alzheimer’s disease (AD) is the most serious and prevalent neurodegenerative disorder still without cure. Since its aetiology is diverse, recent research on anti-AD drugs has been focused on multi-target compounds. In this work, seven novel hybrids (RIV–BIM) conjugating the active moiety of the drug rivastigmine (RIV) with 2 isomeric hydroxyphenylbenzimidazole (BIM) units were developed and studied. While RIV assures the inhibition of cholinesterases, BIM provides further appropriate properties, such as inhibition of amyloid β-peptide (Aβ) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and Aβ42 aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC50 = 32.1 µM), but compounds of series 5 are better inhibitors of BChE (IC50 = 0.9−1.7 µM) than those of series 4. Series 5 also showed good capacity to inhibit self- (42.1−58.7%) and Cu(II)-induced (40.3−60.8%) Aβ aggregation and also to narrow (22.4−42.6%) amyloid fibrils, the relevant compounds being 5b and 5d. Some of these compounds can also prevent the toxicity induced in SH-SY5Y cells by Aβ42 and oxidative stress. Therefore, RIV–BIM hybrids seem to be potential drug candidates for AD with multi-target abilities.

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Section: Resultsmentioning

confidence: 99%

Novel Rivastigmine Derivatives as Promising Multi-Target Compounds for Potential Treatment of Alzheimer’s Disease

et al. 2022

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“…In order to investigate whether compound 5 could be a good candidate as AChE inhibitor, we firstly performed molecular modeling studies. To achieve this goal, the X-ray crystallographic structure of AChE in complex with its inhibitor donepezil (PDB ID: 4EY7) [26] was used. The effectiveness of site-specific molecular docking protocol was checked by re-docking donepezil to AChE into its binding site and by comparing the docked pose (−12.2 kcal/mol) with the co-crystallized ligand, and a root-meansquare deviation (RMSD) value of 0.328 Å was obtained, thus supporting the accuracy of the method.…”

Section: Resultsmentioning

confidence: 99%

4-(4-(((1H-Benzo[d][1,2,3]triazol-1-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)-7-chloroquinoline

Fai

Anyanwu

et al. 2022

Molbank

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The 1,2,3-triazole ring system can be easily obtained by widely used copper-catalyzed click reaction of azides with alkynes. 1,2,3-triazole exhibits myriad of biological activities, including antibacterial antimalarial, and antiviral activities. We herein reported the synthesis of quinoline-based [1,2,3]-triazole hybrid derivative via Cu(I)-catalyzed click reaction of 4-azido-7-chloroquinoline with alkyne derivative of hydroxybenzotriazole (HOBt). The compound was fully characterized by proton nuclear magnetic resonance (1H-NMR), carbon-13 nuclear magnetic resonance (13C-NMR), correlated spectroscopy (1H-1H-COSY), heteronuclear single quantum coherence (HSQC) and distortionless enhancement by polarization transfer (DEPT-135 and DEPT-90) NMR, ultraviolet (UV) and Fourier-transform infrared (FTIR) spectroscopies, and high-resolution mass spectrometry (HRMS). Computational studies were enrolled to predict the interaction of the synthesized compound with acetylcholinesterase, a target of primary relevance for developing new therapeutic options to counteract neurodegeneration. Moreover, the drug-likeness of the compound was also investigated by predicting its pharmacokinetic properties.

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“…Amongst the prepared compounds, 134 displayed the top potent AChE inhibition (IC 50 = 0.059 µM) with mixed type inhibition scenario. Therefore, hybrid 134 may act as potential lead for further construction of selective AChE inhibitors as multifunctional anti-Alzheimer's agents 217 ( Table 5 ).…”

Section: Synthetic Cholinesterase Inhibitorsmentioning

confidence: 99%

Inhibitory potential of nitrogen, oxygen and sulfur containing heterocyclic scaffolds against acetylcholinesterase and butyrylcholinesterase

et al. 2022

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New coumarin-benzotriazole based hybrid molecules as inhibitors of acetylcholinesterase and amyloid aggregation

Cited by 53 publications

References 40 publications

Novel Rivastigmine Derivatives as Promising Multi-Target Compounds for Potential Treatment of Alzheimer’s Disease

Novel Rivastigmine Derivatives as Promising Multi-Target Compounds for Potential Treatment of Alzheimer’s Disease

4-(4-(((1H-Benzo[d][1,2,3]triazol-1-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)-7-chloroquinoline

Inhibitory potential of nitrogen, oxygen and sulfur containing heterocyclic scaffolds against acetylcholinesterase and butyrylcholinesterase

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