Design, synthesis, in-silico and biological evaluation of novel donepezil derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease

Mishra, Chandra Bhushan; Kumari, Shikha; Manral, Apra; Prakash, Amresh; Saini, Vikas; Lynn, Andrew M.; Tiwari, Manisha

doi:10.1016/j.ejmech.2016.09.057

Cited by 92 publications

(40 citation statements)

References 26 publications

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“…Mishra and colleagues (2017) [68] designed and synthesized a novel series of donepezil based multi-functional agents “(E)-5,6-dimethoxy-2-(4-(4-substituted piperazin-1-yl) benzylidene)-2,3-dihydro-1H-inden-1-ones” as potential anti-Alzheimer’s agents. In-vitro studies revealed that these compounds demonstrated moderate to good AChE and amyloid-β aggregation inhibitory activity.…”

Section: Curcumin and Its Derivatives Design And Synthesismentioning

confidence: 99%

“…To elucidate the plausible binding mode of the compounds IP-9, IP-13 and IP-15, molecular docking studies and molecular dynamics simulation studies were also performed and the results indicate their significant interactions with the active sites of AChE as well as Aβ42 peptide. Based on these findings, they conclude that IP-9, IP-13 and IP-15 are potent multi-functional agents against AD and might serve as promising lead candidates for anti-AD drug development [68]. …”

Section: Curcumin and Its Derivatives Design And Synthesismentioning

confidence: 99%

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Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer’s Disease

Reddy

Mańczak

Yin

et al. 2018

JAD

260

133

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The purpose of our article is to assess the current understanding of Indian spice ‘Curcumin’ against amyloid-β (Aβ)-induced toxicity in Alzheimer’s disease (AD) pathogenesis. Natural products, such as ginger, curcumin and gingko biloba have been used as diets and dietary supplements to treat human diseases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes and neurological disorders. Products derived from plants are known to have protective effects, including anti-inflammatory, anti-oxidant, anti-arthritis, pro-healing and boosting memory cognitive functions. In the last decade, several groups have designed and synthesized curcumin and its derivatives and extensively tested using cell and mouse models of AD. Recent research on amyloid-β and curcumin has revealed that curcumin prevents amyloid-β aggregation and crosses the blood brain barrier (BBB), reach brain cells and protect neurons from various toxic insults of aging and amyloid-β in humans. Recent research has also reported that curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD. Further, recent groups have initiated studies on elderly individuals and patients with AD and the outcome of these studies is currently being assessed. This article highlights the beneficial effects of curcumin on AD. This article also critically assesses the current limitations of curcumin’s bioavailability and urgent need for new formulation to increase its brain levels to treat patients with AD.

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Section: Curcumin and Its Derivatives Design And Synthesismentioning

confidence: 99%

Section: Curcumin and Its Derivatives Design And Synthesismentioning

confidence: 99%

Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer’s Disease

Reddy

Mańczak

Yin

et al. 2018

JAD

260

133

View full text Add to dashboard Cite

show abstract

“…232 In silico methods are engaged in many steps of drug development (Figure 20) and the significant role of computer-aided drug design is highlighted in the steps of hit identification and lead optimization of many therapeutic agents for the treatment of cancers, [233][234][235] infections, [236][237][238][239] metabolic diseases, 237,240 and diseases of the CNS. [241][242][243] Amongst the available computational approaches, quantitative structure-activity relationship (QSAR) is a robust tool that plays an important role in drug development and provide useful information for guiding design and synthesis of pharmacologically active molecules and are thus highly effective in terms of saving time and cost as well as in increasing the success rate of development. 244 These technologies are fundamentally used for screening of novel scaffolds as well as for prioritizing the compounds from large libraries for further investigation and development.…”

Section: Roles Of Computational Approaches For Targeting Secretasesmentioning

confidence: 99%

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Schaduangrat

Prachayasittikul

Choomwattana

et al. 2019

Medicinal Research Reviews

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The continual increase of the aging population worldwide renders Alzheimer's disease (AD) a global prime concern. Several attempts have been focused on understanding the intricate complexity of the disease's development along with the on‐ andgoing search for novel therapeutic strategies. Incapability of existing AD drugs to effectively modulate the pathogenesis or to delay the progression of the disease leads to a shift in the paradigm of AD drug discovery. Efforts aimed at identifying AD drugs have mostly focused on the development of disease‐modifying agents in which effects are believed to be long lasting. Of particular note, the secretase enzymes, a group of proteases responsible for the metabolism of the β‐amyloid precursor protein (βAPP) and β‐amyloid (Aβ) peptides production, have been underlined for their promising therapeutic potential. This review article attempts to comprehensively cover aspects related to the identification and use of drugs targeting the secretase enzymes. Particularly, the roles of secretases in the pathogenesis of AD and their therapeutic modulation are provided herein. Moreover, an overview of the drug development process and the contribution of computational (in silico) approaches for facilitating successful drug discovery are also highlighted along with examples of relevant computational works. Promising chemical scaffolds, inhibitors, and modulators against each class of secretases are also summarized herein. Additionally, multitarget secretase modulators are also taken into consideration in light of the current growing interest in the polypharmacology of complex diseases. Finally, challenging issues and future outlook relevant to the discovery of drugs targeting secretases are also discussed.

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“…Amino acids of the PAS interact with cationic ammonium substrates and direct them inwards the gorge to the catalytic triad. Considering the important role played by PAS, Scientists have employed bivalent approach targeting both PAS and CAS regions with considerable success . These molecules have offered high selectivity which is critical for a good drug.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Design, synthesis, in-silico and biological evaluation of novel donepezil derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease

Cited by 92 publications

References 26 publications

Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer’s Disease

Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer’s Disease

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

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

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