Development of Piperazinediones as dual inhibitor for treatment of Alzheimer's disease

Kumar, Devendra; Gupta, Sukesh Kumar; Ganeshpurkar, Ankit; Gutti, Gopichand; Krishnamurthy, Sairam; Modi, Gyan; Singh, Suman Kumar

doi:10.1016/j.ejmech.2018.02.078

Cited by 64 publications

(25 citation statements)

References 42 publications

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“…In spite of drugs aimed at relieving the symptoms of AD, patients have been widely studied for a long time, which has largely been ineffective or inconclusive ultimately due to a variety of reasons [ 14 ]. For example, the drug that targets Aβ has been proved to provide symptomatic relief for only the initial 1–2 years, but is incapable of preventing or delaying the progression of the AD pathology fundamentally [ 8 , 15 ]. With the changes in dietary structure and the increase of life expectancy, AD has become the most devastating neurodegenerative disorder characterized by a high morbidity rate and mortality [ 14 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Roles and Mechanisms of the Protein Quality Control System in Alzheimer’s Disease

Liu

Ding

et al. 2021

IJMS

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Alzheimer’s disease (AD) is characterized by the deposition of senile plaques (SPs) and the formation of neurofibrillary tangles (NTFs), as well as neuronal dysfunctions in the brain, but in fact, patients have shown a sustained disease progression for at least 10 to 15 years before these pathologic biomarkers can be detected. Consequently, as the most common chronic neurological disease in the elderly, the challenge of AD treatment is that it is short of effective biomarkers for early diagnosis. The protein quality control system is a collection of cellular pathways that can recognize damaged proteins and thereby modulate their turnover. Abundant evidence indicates that the accumulation of abnormal proteins in AD is closely related to the dysfunction of the protein quality control system. In particular, it is the synthesis, degradation, and removal of essential biological components that have already changed in the early stage of AD, which further encourages us to pay more attention to the protein quality control system. The review mainly focuses on the endoplasmic reticulum system (ERS), autophagy–lysosome system (ALS) and the ubiquitin–proteasome system (UPS), and deeply discusses the relationship between the protein quality control system and the abnormal proteins of AD, which can not only help us to understand how and why the complex regulatory system becomes malfunctional during AD progression, but also provide more novel therapeutic strategies to prevent the development of AD.

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Section: Introductionmentioning

confidence: 99%

Roles and Mechanisms of the Protein Quality Control System in Alzheimer’s Disease

Liu

Ding

et al. 2021

IJMS

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“…Crystal structural studies with both AChE enzyme have revealed that they have different binding sites, containing the aromatic patch (AP), oxyanionic hole, peripheral anionic site (PAS), catalyist active site (CAS), acyl site and anionic site (AS). To improve effective acetylcholinesterase inhibitors (AChEI), acetylcholinesterase activity must be inhibited in the oxidation hole region (AS) and in the peripheral anionic region (PAS), because it causes accumulation of bound AChE amyloid peptide plaques in PAS [9,10,11,12,13,14,15,16,17]. Although there are many ongoing studies for the treatment of AD, only some drugs have been accepted by the FDA, such as donepezil, rivastigmin and tacrine [18].…”

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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“…The piperazine ring could be evaluated as a bioisostere of the piperazine ring, considering the molecular framework of the anticholinesterase drug donepezil . Literature survey also supports the enzyme inhibitory efficiency of piperazine derivatives confirmed by many studies …”

Section: Introductionmentioning

confidence: 56%

Novel thiazole‐piperazine derivatives as potential cholinesterase inhibitors

Demirayak

Şahin

Ertaş

et al. 2019

Journal of Heterocyclic Chem

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Dementia is a cognitive disorder mostly associated with Alzheimer's disease (AD) in addition to being seen in many other diseases of the central nervous system (CNS). The limited number of drugs is not sufficient to provide adequate improvement to increase the quality of life of patients suffering from this symptom; therefore, all treatment options should be evaluated in detail. In this study, new molecules, [2‐(4‐(2/3/4‐substituted phenyl)piperazin‐1‐yl)‐4‐phenylthiazol‐5‐yl][3/4‐substituted phenyl]methanone derivatives (1‐44), were obtained and analyzed in terms of their anticholinesterase activities. Kinetic mode and molecular interactions were also evaluated. An enzyme inhibition study was undertaken on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using the Ellman method. Maestro program was used in molecular modeling studies. Forty‐four compounds were evaluated on AChE and BChE enzymes at 10−3 and 10−4 concentrations. The inhibition concentrations were calculated as 0.268μM to 2.104μM for six compounds (4, 5, 16, 27, 37, and 38) on AChE. Compound 5 including the 4‐methoxy substituent (IC50: 0.268μM) and compound 38 containing the 4‐methoxy and 3‐methyl substituents (IC50: 0.286μM) showed the highest AChE inhibitory activity. They were further examined in terms of hydrogen bonding with Arg296 and Ar‐Ar interaction with Trp286. The activity of compound 5 was also assessed in mixed‐type kinetic mode.

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Development of Piperazinediones as dual inhibitor for treatment of Alzheimer's disease

Cited by 64 publications

References 42 publications

Roles and Mechanisms of the Protein Quality Control System in Alzheimer’s Disease

Roles and Mechanisms of the Protein Quality Control System in Alzheimer’s Disease

Synthesis and AChE-Inhibitory Activity of New Benzimidazole Derivatives

Novel thiazole‐piperazine derivatives as potential cholinesterase inhibitors

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