Synthesis of novel chromenones linked to 1,2,3-triazole ring system: Investigation of biological activities against Alzheimer’s disease

Saeedi, Mina; Safavi, Maliheh; Karimpour-Razkenari, Elahe; Mahdavi, Mohammad; Edraki, Najmeh; Moghadam, Farshad Homayouni; Khanavi, Mahnaz; Akbarzadeh, Tahmineh

doi:10.1016/j.bioorg.2016.11.011

Cited by 66 publications

(19 citation statements)

References 22 publications

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“…Despite the good results obtained in silico analysis, it is mandatory to perform biological tests in vitro and in vivo. It should be noted that in addition to the compounds analyzed, similar series of 1,3,4-thiadiazole and 1,2,4-triazole derivatives should be studied, since their derivatives also have activity against Alzheimer's disease [21,22].…”

Section: Discussionmentioning

confidence: 99%

MOLECULAR DOCKING STUDIES OF SOME N-Amidoalkylated DERIVATIVES OF 2-Amino-1,3,4-Oxadiazole AS POTENTIAL INHIBITORS OF GLYCOGEN SYNTHASE KINASE-3β

Zadorozhnii

Pokotylo

2018

Technology transfer: innovative solutions in medicine

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Alzheimer's disease is a neurodegenerative disease characterized by pathological features of neurofibrillary tangles and β-amyloid plaques in the cerebral cortex. In Alzheimer's disease, tau protein undergoes excess phosphorylation, due to which its threads begin to merge and form neurofibrillary tangles within nerve cells. It has been shown that glycogen synthase kinase-3β is a key factor in the phosphorylation of tau protein, its increased activity leading to pathologies of neurofibrillary tangles and, consequently, to neurodegenerative changes in the brain. In this connection, the search for effective inhibitors of GSK-3β is a very important and urgent task, for their further use in the treatment of Alzheimer's disease. Aim of research. The aim of this study is to search new inhibitors of GSK-3β among N-amidoalkylated derivatives of 2-amino-1,3,4-oxadiazole by molecular docking methods. Materials and methods. We have carried out geometry optimization of analyzed structures within PM3 semi-empirical method, and GSK-3β molecular docking using software ArgusLab 4.0.1. The three-dimensional crystal structure of co-crystallizer GSK-3β and inhibitor has been loaded from the data bank of protein molecules (PDB ID: 3F7Z). Results. In this study it has been shown that the structures being studied mainly form stronger complexes with the enzyme compared to the known inhibitor. Based on the results of molecular docking, the compounds leaders N-(((5-(2-bromophenyl)-1,3,4-oxadiazol-2-yl)amino)methyl)benzamide and 2,4-dichloro-N-(2,2,2-trichloro-1-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)amino)ethyl)benzamide have been chosen. The structures of the compounds leaders have been tested for compliance with Lipinski criteria. Conclusions. Proposed compounds leaders can be recommended for further studies in the treatment of Alzheimer's disease. Despite the good results obtained in silico analysis, it is mandatory to perform biological tests in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

MOLECULAR DOCKING STUDIES OF SOME N-Amidoalkylated DERIVATIVES OF 2-Amino-1,3,4-Oxadiazole AS POTENTIAL INHIBITORS OF GLYCOGEN SYNTHASE KINASE-3β

Zadorozhnii

Pokotylo

2018

Technology transfer: innovative solutions in medicine

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“…[20 -23] For example, coumarin-3-carboxamides A and B were found to be potent anti-AChE inhibitors that interact with both CS and PAS of AChE (Figure 1). [24,25] On the other hands, N-morpholine moiety was recently used in design and synthesis of new AChE inhibitors (Figure 1, C). [26] Hence, in continuation to our interest in the development of potent anti-Alzheimer agents by molecular hybridization, in this work, a novel series of coumarin-3-carboxamide-N-morpholine hybrids 5a-5l has been presented ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Cholinesterase Inhibition Assay of Coumarin‐3‐carboxamide‐N‐morpholine Hybrids as New Anti‐Alzheimer Agents

Tehrani

Rezaei

Asadi

et al. 2019

Chemistry & Biodiversity

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A new series of coumarin‐3‐carboxamide‐N‐morpholine hybrids 5a–5l was designed and synthesized as cholinesterases inhibitors. The synthetic approach for title compounds was started from the reaction between 2‐hydroxybenzaldehyde derivatives and Meldrum's acid to afford corresponding coumarin‐3‐carboxylic acids. Then, amidation of the latter compounds with 2‐morpholinoethylamine or N‐(3‐aminopropyl)morpholine led to the formation of the compounds 5a–5l. The in vitro inhibition screen against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) revealed that most of the synthesized compounds had potent AChE inhibitory while their BuChE inhibitions are moderate to weak. Among them, propylmorpholine derivative 5g (N‐[3‐(morpholin‐4‐yl)propyl]‐2‐oxo‐2H‐chromene‐3‐carboxamide) bearing an unsubstituted coumarin moiety and ethylmorpholine derivative 5d (6‐bromo‐N‐[2‐(morpholin‐4‐yl)ethyl]‐2‐oxo‐2H‐chromene‐3‐carboxamide) bearing a 6‐bromocoumarin moiety showed the most activity against AChE and BuChE, respectively. The inhibitory activity of compound 5g against AChE was 1.78 times more than that of rivastigmine and anti‐BuChE activity of compound 5d is approximately same as rivastigmine. Kinetic and docking studies confirmed the dual binding site ability of compound 5g to inhibit AChE.

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“…In this respect, design, synthesis, and biological evaluation of multi-target heterocycles have been the center of attention to develop potent and novel anti-AD drugs [10 -12] as well as diagnostic applications. [13,14] Focusing on the cholinesterase inhibitory activity of heterocycles, design and synthesis of a wide range of compounds such as coumarins, [15] 1,2,3-triazoles, [16][17][18][19] isoxazoles, [19,20] imidazoles, [21] pyrazoles, [22] and quinazolines, [23] etc., have been developed. In this work, following anti-ChE activity of our previously reported isoxazole derivatives A and B, [19,20] synthesis and biological evaluation of novel isoxazoles connected to phenylpiperazine moiety were reported ( Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Selective Acetylcholinesterase Inhibitors: Arylisoxazole‐Phenylpiperazine Derivatives

Saeedi

Mohtadi-Haghighi

Mirfazli

et al. 2019

Chemistry & Biodiversity

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In this work, a novel series of arylisoxazole-phenylpiperazines were designed, synthesized, and evaluated toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Our results revealed that [5-(2chlorophenyl)-1,2-oxazol-3-yl](4-phenylpiperazin-1-yl)methanone (5c) was the most potent AChE inhibitor with IC 50 of 21.85 μM. It should be noted that most of synthesized compounds showed no BChE inhibitory activity and [5-(2-fluorophenyl)-1,2-oxazol-3-yl](4-phenylpiperazin-1-yl)methanone (5a) was the most active anti-BChE derivative (IC 50 = 51.66 μM). Also, kinetic studies for the AChE and BChE inhibitory activity of compounds 5c and 5a confirmed that they have simultaneously bound to the catalytic site (CS) and peripheral anionic site (PAS) of both AChE and BChE. Furthermore, docking study of compound 5c showed desired interactions of that compound with amino acid residues located in the active and peripheral anionic sites. Compound 5c was also evaluated for its BACE1 inhibitory activity and demonstrated IC 50 = 76.78 μM. Finally, neuroprotectivity of compound 5c on Aβ-treated neurotoxicity in PC12 cells depicted low activity.

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Synthesis of novel chromenones linked to 1,2,3-triazole ring system: Investigation of biological activities against Alzheimer’s disease

Cited by 66 publications

References 22 publications

MOLECULAR DOCKING STUDIES OF SOME N-Amidoalkylated DERIVATIVES OF 2-Amino-1,3,4-Oxadiazole AS POTENTIAL INHIBITORS OF GLYCOGEN SYNTHASE KINASE-3β

MOLECULAR DOCKING STUDIES OF SOME N-Amidoalkylated DERIVATIVES OF 2-Amino-1,3,4-Oxadiazole AS POTENTIAL INHIBITORS OF GLYCOGEN SYNTHASE KINASE-3β

Design, Synthesis, and Cholinesterase Inhibition Assay of Coumarin‐3‐carboxamide‐N‐morpholine Hybrids as New Anti‐Alzheimer Agents

Design and Synthesis of Selective Acetylcholinesterase Inhibitors: Arylisoxazole‐Phenylpiperazine Derivatives

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