N-Cyclohexylimidazo[1,2-a]pyridine derivatives as multi-target-directed ligands for treatment of Alzheimer's disease

Haghighijoo, Zahra; Akrami, Sara; Saeedi, Mina; Zonouzi, Afsaneh; Iraji, Aida; Larijani, Bagher; Fakherzadeh, Hossein; Sharifi, Farshad; Arzaghi, Seyed Masoud; Mahdavi, Mohammad

doi:10.1016/j.bioorg.2020.104146

Cited by 26 publications

(12 citation statements)

References 39 publications

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“…Donepezil, galantamine, and rivastigmine, as well as huperzine A are approved AChE inhibitors that increase acetylcholine levels at synapses and improve neurotransmission. In this context, search for novel AChE inhibitors ongoing and novel scaffolds including dioxane-4,6-dione 9 , thiourea 10,11 , arylisoxazole 12 , thio methyltriazole were developed 10,[13][14][15][16] .…”

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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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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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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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“…One of the most efficient ones is OM99‐2 with an IC 50 value of 14.7 nM. [ 14 ] However, due to poor physicochemical and pharmaceutical properties, including insufficient oral bioavailability, short serum half‐life, and low blood–brain barrier penetration, there is an ongoing interest to design small‐molecule BACE1 inhibitors. [ 3 ] For the past few years, there have been many synthetic BACE1 inhibitors; among such compounds, there are limited examples of the isoxazole‐3‐carboxamides molecular skeleton as the core structure.…”

Section: Resultsmentioning

confidence: 99%

Novel N‐benzylpiperidine derivatives of 5‐arylisoxazole‐3‐carboxamides as anti‐Alzheimer's agents

Saeedi

Felegari

Iraji

et al. 2020

Archiv der Pharmazie

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The complex pathophysiology of Alzheimer's disease (AD) has prompted researchers to develop multitarget‐directed molecules to find an effective therapy against the disease. In this context, a novel series of N‐(1‐benzylpiperidin‐4‐yl)‐5‐arylisoxazole‐3‐carboxamide derivatives were designed, synthesized, and evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). In vitro biological evaluation demonstrated that compound 4e was the best AChE (IC50 = 16.07 μM) and BuChE inhibitor (IC50 = 15.16 μM). A kinetic study of 4e was also conducted, which presented a mixed‐type inhibition for both enzymes. Molecular docking studies revealed that compound 4e fitted well into the active sites of AChE and BuChE, forming stable and strong interactions with key residues Glu199, Trp84, Asp72, Tyr121, and Phe288 in AChE and His438, Trp82, Ala328, Tyr332, Phe329, Thr120, and Pro285 in BuChE. Besides, the inhibition of BACE1 by 4e and the biometal chelation activity of 4e were measured. The neuroprotective assessment revealed that 4e exhibited 23.2% protection at 50 µM toward amyloid‐beta‐induced PC12 neuronal cells. Overall, this study exhibited that compound 4e was a promising compound targeting multiple factors associated with AD.

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“…Ресвератрол снижает агрегацию отложений Aβ через активацию неамилоидогенного пути расщепления АРР и выведения Aβ, а также активирует микроглию в гиппокампе и коре трансгенных мышей APP/PS1 [209]. Перспективные соединения, проявляющие одновременно антиоксидантную активность и способность ингибировать BACE1, выявлены среди производных стирилбензамида [210], N-циклогексилимидазо[1,2-a]пиридина [211] и галогенированных производных триметоксихалкона [212,213].…”

Section: потенциальные нейропротекторные препараты воздействующие одн...unclassified

The Role of a Pathological Interaction between β-amyloid and Mitochondria in the Occurrence and Development of Alzheimer’s Disease

et al. 2022

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Alzheimers disease (AD) is one of the most common neurodegenerative diseases in existence. It is characterized by an impaired cognitive function that is due to a progressive loss of neurons in the brain. Extracellular -amyloid (A) plaques are the main pathological features of the disease. In addition to abnormal protein aggregation, increased mitochondrial fragmentation, altered expression of the genes involved in mitochondrial biogenesis, disruptions in the ERmitochondria interaction, and mitophagy are observed. Reactive oxygen species are known to affect A expression and aggregation. In turn, oligomeric and aggregated A cause mitochondrial disorders. In this review, we summarize available knowledge about the pathological effects of A on mitochondria and the potential molecular targets associated with proteinopathy and mitochondrial dysfunction for the pharmacological treatment of Alzheimers disease.

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N-Cyclohexylimidazo[1,2-a]pyridine derivatives as multi-target-directed ligands for treatment of Alzheimer's disease

Cited by 26 publications

References 39 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

Novel N‐benzylpiperidine derivatives of 5‐arylisoxazole‐3‐carboxamides as anti‐Alzheimer's agents

The Role of a Pathological Interaction between β-amyloid and Mitochondria in the Occurrence and Development of Alzheimer’s Disease

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