P.8.b.001 Interaction of acetylcholinesterase reactivators with albumin

Zemek, Filip; Sepsova, V.; Drtinová, Lucie; Korábečný, Jan; Pohanka, Miroslav; Karasová, Jana Žďárová; Kuča, Kamil

doi:10.1016/s0924-977x(12)70690-9

Cited by 15 publications

(26 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Over the last decades, drug discovery projects were mainly focused on the cholinergic, the amyloid or the tau hypothesis . However, none of the new drug candidates have a real impact on the outcome of the disease . The multifactorial origin of AD encouraged new approaches for drug design, as multitarget design programs .…”

Section: Introductionmentioning

confidence: 99%

Novel Coumarin‐Quinoline Hybrids: Design of Multitarget Compounds for Alzheimer's Disease

et al. 2019

View full text Add to dashboard Cite

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, presenting the most devastating consequences on human health and life quality. Coumarin‐quinoline hybrids were synthesized following a very efficient and versatile strategy. Small structural variations contributed to dual acetyl/butyrylcholinesterases (AChE/BuChE) activity or selectivity towards one of these enzymes. In addition, some of the studied compounds are interesting iron chelators, presenting a tendency to be neuroprotective. Moreover, the compounds are not cytotoxic for SH‐SY5Y neuroblastoma cells. Compound 9c proved to be the most interesting compound of the studied series. This compound is selective against AChE and proved to be an excellent iron chelating agent (iron chelation at 100 μM=72.87%). Molecular docking studies were performed to establish the nature of the interaction between the studied compounds and the binding pockets, leading to a rationalization of structure–activity relationships. Compound 9c forms a well‐defined π‐stacking interaction with Phe330 and interacts with Tyr121 residue via a hydrogen bond, while the inactive compounds cannot establish these interactions. Important preliminary results against different targets, as well as some structure–activity relationships, were concluded from the experimental results.

show abstract

Section: Introductionmentioning

confidence: 99%

Novel Coumarin‐Quinoline Hybrids: Design of Multitarget Compounds for Alzheimer's Disease

et al. 2019

View full text Add to dashboard Cite

show abstract

“…It affects millions of people above 65 and the numbers of sufferers are still increasing. It is estimated that by 2030 65.7 million people will be affected by this disease ,. Its symptoms are recognized as a loss of memory, progressive cognitive impairment, personality changes and behavioral disturbances and disorientation .…”

Section: Introductionmentioning

confidence: 99%

Phyto‐Tacrine Hybrids as Promising Drugs to Treat Alzheimer's Disease

Girek

2019

ChemistrySelect

View full text Add to dashboard Cite

Alzheimer's disease is an incurable neurodegenerative disease which represents the most common form of dementia. Cognition impairment and memory loss are mostly caused by reduced levels of the neurotransmitter acetylcholine. Therefore, current drug therapies are based on the cholinergic hypothesis. However, β‐amyloid hypothesis is getting more important in last years. For many years, one of the basic drugs for the treatment of Alzheimer's disease was tacrine, acetylcholinesterase inhibitor. Unfortunately, it was withdrawn from the market due to its side effects. To diminish side effects, research has focused on obtaining multi‐target‐directed ligands, which target numerous disease pathways simultaneously, including those of Alzheimer's disease. The comprehensive review is focused on the outcomes of the studies of phyto‐tacrine hybrids. Hybrids can inhibit cholinesterase and β‐amyloid aggregation. Additionally, phyto‐hybrids have neuroprotective, anti‐inflammatory, hepatoprotective and metal chelating properties. Further research is necessary for the development of hybrids to find a proper therapy for Alzheimer's disease.

show abstract

“…The PAS site in AChE is the nucleation centre for accumulation of amyloid β and thus, it offers a good target to design drugs aimed at blocking amyloid fibril formation . Clearly, AChE is at the centre of both amyloid and cholinergic hypotheses which in turn suggests that these hypotheses are neither independent and nor mutually exclusive.…”

Section: Introductionmentioning

confidence: 99%

Pyrimidine‐Triazolopyrimidine and Pyrimidine‐Pyridine Hybrids as Potential Acetylcholinesterase Inhibitors for Alzheimer's Disease

et al. 2018

View full text Add to dashboard Cite

Acetylcholinesterase (AChE) is a critical enzyme, in Alzheimer's disease (AD) progression and hence has been subjected to intense drug discovery programme. Here, we report synthesis and testing of pyrimidine derivatives in conjugation with triazolopyrimidine based hybrid scaffold of AChE inhibitors for development of new molecules towards the treatment of AD. We used a multipronged approach employing computational, chemical and biological approaches to find the best inhibitor of AChE. Three molecules (10 e, 11 c and 12 b) derived from this scaffold inhibited AChE in nanomolar to micromolar range. Highest activity was shown by 2‐(4‐(6‐(quinolin‐8‐yloxy)pyrimidin‐4‐yl) piperazin‐1‐yl)nicotinonitrile (12 b) which has IC50 value of 36 nM. Inhibitory effect of 12 b was stronger for human AChE in neuronal cell extract compared to eelAChE. This activity is comparable to donepezil (IC50=38nM) which is considered as good standard among AChE inhibitors. The inhibitory activity of 12 b was also in agreement with molecular simulation studies which showed stable interaction of the 12 b with the catalytic active site as well as peripheral anionic site. Molecular simulation studies also indicated stronger interaction of 12 b with rhAChE than TcAChE. This was later confirmed in studies with neuronal cell extract where compound 12 b showed enzyme inhibition at 25 nM. Further this molecule was not found to be toxic or carcinogenic.

show abstract

P.8.b.001 Interaction of acetylcholinesterase reactivators with albumin

Cited by 15 publications

References 0 publications

Novel Coumarin‐Quinoline Hybrids: Design of Multitarget Compounds for Alzheimer's Disease

Novel Coumarin‐Quinoline Hybrids: Design of Multitarget Compounds for Alzheimer's Disease

Phyto‐Tacrine Hybrids as Promising Drugs to Treat Alzheimer's Disease

Pyrimidine‐Triazolopyrimidine and Pyrimidine‐Pyridine Hybrids as Potential Acetylcholinesterase Inhibitors for Alzheimer's Disease

Contact Info

Product

Resources

About