Synthesis and biological evaluation of new N-benzylpyridinium-based benzoheterocycles as potential anti-Alzheimer’s agents

Salehi, Naeimeh; Mirjalili, Bi Bi Fatemeh; Nadri, Hamid; Abdolahi, Zahra; Forootanfar, Hamid; Samzadeh‐Kermani, Alireza; Küçükkılınç, Tuba Tüylü; Ayazgök, Beyza; Emami, Saeed; Haririan, Ismaeil; Sharifzadeh, Mohammad; Foroumadi, Alireza; Khoobi, Mehdi

doi:10.1016/j.bioorg.2018.11.010

Cited by 31 publications

(12 citation statements)

References 30 publications

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“…Compounds A-F (Fig. 2) are some AChE examples [53][54][55][56][57][58][59] . However, those inhibitors that possess a positive charge (quaternary amines) are mostly unable to cross the blood-brain barrier (BBB) and show poor efficiency in CNS.…”

Section: Resultsmentioning

confidence: 99%

Design, synthesis, in silico and biological evaluations of novel polysubstituted pyrroles as selective acetylcholinesterase inhibitors against Alzheimer’s disease

Pourtaher

Hasaninejad

Iraji

2022

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The objective of this study was to design new polysubstituted pyrrole derivatives as selective acetylcholinesterase (AChE) inhibitors to target Alzheimer's disease. In this context, a highly efficient, one-pot, sequential, multi-component synthesis of a diverse range of polysubstituted pyrroles was developed through a sequential domino strategy by the condensation of amines with 1,1-bis(methylthio)-2-nitroethene (BMTNE), Knovenagle reaction of arylglyoxals with malono derivatives and subsequent Michael addition and intramolecular cyclization reaction in EtOH at reflux. Thirty-nine synthesized compounds were evaluated as AChE and butyrylcholinesterase (BChE) inhibitors. Among the synthesized compounds, compound 4ad (IC50 = 2.95 ± 1.31 µM) was the most potent and selective AChE inhibitor with no significant inhibition against butyrylcholinesterase BChE. A kinetic study of 4ad revealed that this compound inhibited AChE in an uncompetitive mode. Based on a molecular modeling study, compound 4ad due to its small size properly fitted into the active site of AChE compared to BChE and stabilized by H-bond and hydrophobic interactions with the critical residues of the AChE binding pocket. Consequently, it was proposed that the 4ad derivative can be an ideal lead candidate against AD with a simple and practical operation of synthetic procedures.

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Section: Resultsmentioning

confidence: 99%

Design, synthesis, in silico and biological evaluations of novel polysubstituted pyrroles as selective acetylcholinesterase inhibitors against Alzheimer’s disease

Pourtaher

Hasaninejad

Iraji

2022

Sci Rep

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“…This property facilitated a systematic investigation [19,20,21]. When the literature studies are evaluated, it can be learned that benzazole derivatives have inhibitory activity on acetylcholinesterase enzyme [17,22,23,24,25,26,27,28,29,30]. In addition, some benzimidazole derivatives have been shown to be useful as amyloid imaging probes because of their high binding affinity to Aβ aggregates and high uptake into the brain [31].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and AChE-Inhibitory Activity of New Benzimidazole Derivatives

et al. 2019

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Alzheimer’s disease (AD), one of the main causes of aged dementia, is a progressive and degenerative neurological disorder characterized by loss of cognition and memory. Although the symptomatic treatment of AD, particularly acetylcholinesterase inhibitors (AChEIs) based on the ‘cholinergic hypothesis’, has been successful in clinic, at present there is no cure for this disease. In this study, we designed compounds carrying benzimidazole and triazole rings on the same chemical skeleton so as to investigate their potential acetylcholinesterase and butyrylcholinesterase activity. Furthermore, molecular modeling study was performed to determine the binding mode of the best inhibitor to the AChE. Among them, compounds 3d and 3h, which featured 3,4-dihydroxy substitution at the phenyl ring and 5(6)-chloro substitution at the benzimidazole ring were found to be potent inhibitors of AChE. The inhibition kinetics of the two most active derivatives 3d and 3h were further studied. The kinetic displayed increasing slope and increasing intercept, which is consistent with a mixed inhibition. The IC50 and Ki values of 3d are 31.9 ± 0.1 nM and 26.2 nM, respectively. Compound 3h exhibited IC50 of 29.5 ± 1.2 nM and Ki of 24.8 nM. The above data compared favorably with data for donepezil (21.8 ± 0.9 nM) the reference compound in our study.

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“…In this work and for further progressing in our research program on the discovery of new coumarin derivatives as MTDLs against AD ( Jalili-Baleh et al, 2018a ; Salehi et al, 2019 ), we prepared new 3-arylcoumarin derivatives bearing N -benzyl triazole substructures ( Figure 1 ) to target 15-LOX and ChEs, with neuroprotection activity and anti-Aβ aggregation activity, simultaneously. Most of the previously published studies tried to improve the ChE inhibition and neuroprotection/antioxidant activities of the coumarin backbone by conjugation of the appropriate pharmacophores.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of New 3-Arylcoumarins Bearing N-Benzyl Triazole Moiety: Dual Lipoxygenase and Butyrylcholinesterase Inhibitors With Anti-Amyloid Aggregation and Neuroprotective Properties Against Alzheimer’s Disease

et al. 2022

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A novel series of coumarin derivatives linked to the N-benzyl triazole group were synthesized and evaluated against 15-lipoxygenase (15-LOX), and acetyl- and butyrylcholinesterase (AChE and BuChE) to find the most potent derivative against Alzheimer’s disease (AD). Most of the compounds showed weak to moderate activity against ChEs. Among the most active BuChE and 15-LOX inhibitors, 8l and 8n exhibited an excellent neuroprotective effect, higher than the standard drug (quercetin) on the PC12 cell model injured by H2O2 and significantly reduced aggregation of amyloid Aβ1-42, with potencies of 1.44 and 1.79 times higher than donepezil, respectively. Compound 8l also showed more activity than butylated hydroxytoluene (BHT) as the reference antioxidant agent in reducing the levels of H2O2 activated by amyloid β in BV2 microglial cells. Kinetic and ligand–enzyme docking studies were also performed for better understanding of the mode of interaction between the best BuChE inhibitor and the enzyme. Considering the acceptable BuChE and 15-LOX inhibition activities as well as significant neuroprotection, and anti-amyloid aggregation activities, 8l and 8n could be considered as potential MTDLs for further modification and studies against AD.

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Synthesis and biological evaluation of new N-benzylpyridinium-based benzoheterocycles as potential anti-Alzheimer’s agents

Cited by 31 publications

References 30 publications

Design, synthesis, in silico and biological evaluations of novel polysubstituted pyrroles as selective acetylcholinesterase inhibitors against Alzheimer’s disease

Design, synthesis, in silico and biological evaluations of novel polysubstituted pyrroles as selective acetylcholinesterase inhibitors against Alzheimer’s disease

Synthesis and AChE-Inhibitory Activity of New Benzimidazole Derivatives

Synthesis of New 3-Arylcoumarins Bearing N-Benzyl Triazole Moiety: Dual Lipoxygenase and Butyrylcholinesterase Inhibitors With Anti-Amyloid Aggregation and Neuroprotective Properties Against Alzheimer’s Disease

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