Discovery of novel propargylamine-modified 4-aminoalkyl imidazole substituted pyrimidinylthiourea derivatives as multifunctional agents for the treatment of Alzheimer's disease

Xu, Yixiang; Wang, Huan; Li, Xiaokang; Dong, Shengnan; Liu, Wenwen; Gong, Qi; Wang, Tianduanyi; Tang, Yun; Zhu, Jin; Li, Jian; Zhang, Haiyan; Mao, Fei

doi:10.1016/j.ejmech.2017.08.025

Cited by 60 publications

(36 citation statements)

References 51 publications

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“…When Aβ aggregates to form brain sediments, it causes neurodegenerative diseases, leading to clinically observed loss of patient memory and cognitive ability. Aβ aggregation can cause a series of pathological changes, which ultimately induces cytotoxicity and cell death, including mitochondria‐dependent apoptosis . Studies have shown that some drugs for Alzheimer's disease treatment may cause cytotoxicity (eg, tacrine can cause significant hepatotoxicity); therefore, we aimed to find a new drug that can inhibit nerve cell apoptosis and thus become a safer option for the treatment of Alzheimer's disease …”

Section: Introductionmentioning

confidence: 99%

Treatment of Alzheimer's disease with framework nucleic acids

et al. 2020

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Objectives To provide a new research direction for nerve regeneration and strategy for Alzheimer's disease treatment, tetrahedral DNA nanostructures (TDNs)—novel tetrahedral framework nucleic acid molecule nanoparticles (tFNA) that can inhibit the apoptosis of nerve cells are employed in the experiment. Materials and methods To verify the successful preparation of TDNs, the morphology of TDNs was observed by atomic force microscopy (AFM) and transmission electron microscopy (TEM). The expression of apoptosis‐related genes and proteins was investigated by confocal microscope, flow cytometry, PCR and Western blot to detect the impact of TDNs on the Alzheimer's model. And finally, Morris water maze experiment was used to test behavioural changes and Nissl stain was detected to observe the morphology and quantity of neurons in the hippocampus. Immunofluorescence stain was used to observe the Aβ stain, and TUNEL dyeing was utilized to observe neuronal apoptosis. Results In vitro and in vivo experiments confirm that TDNs, in a specific concentration range, have no toxic or side effects on nerve cells, can effectively inhibit apoptosis in an Alzheimer's disease cell model and effectively improve memory and learning ability in a rat model of Alzheimer's disease. Conclusions These findings suggest that TDNs may be a promising drug for the treatment of Alzheimer's disease.

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Section: Introductionmentioning

confidence: 99%

Treatment of Alzheimer's disease with framework nucleic acids

et al. 2020

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“…Sang et al reported a series of chalcone-O-carbamate derivatives (20, Figure 7) potentially able to behave as ChEs and MAO-A/MAO-B inhibitors and endowed with antioxidant activities, anti Aβ 42 aggregation and metal-chelating properties, and neuroprotective effects against H 2 O 2 -induced PC12 cell injury [45]. The new compounds are designed to combine the interesting biological activities of chalcones [46] with the well-known AChE and BuChE inhibitory Figure 7) as ChE and MAO inhibitors [47]. In more detail, they combined the imidazole-substituted pyrimidinylthiourea moiety (AChE inhibitor pharmacophore) with the propargylamine group of Selegiline (MAO-B inhibitor pharmacophore), spaced by different linkers.…”

Section: Dual Che and Mao Inhibitorsmentioning

confidence: 99%

“…Xu et al have also presented a nice example of propargylamine-modified scaffolds ( 21 , Figure 7 ) as ChE and MAO inhibitors [ 47 ]. In more detail, they combined the imidazole-substituted pyrimidinylthiourea moiety (AChE inhibitor pharmacophore) with the propargylamine group of Selegiline (MAO-B inhibitor pharmacophore), spaced by different linkers.…”

Section: Target Combinations In Mtdl Design Strategy For Admentioning

confidence: 99%

Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

Maramai

Benchekroun

Gabr

et al. 2020

BioMed Research International

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Neurodegenerative diseases represent nowadays one of the major health problems. Despite the efforts made to unveil the mechanism leading to neurodegeneration, it is still not entirely clear what triggers this phenomenon and what allows its progression. Nevertheless, it is accepted that neurodegeneration is a consequence of several detrimental processes, such as protein aggregation, oxidative stress, and neuroinflammation, finally resulting in the loss of neuronal functions. Starting from these evidences, there has been a wide search for novel agents able to address more than a single event at the same time, the so-called multitarget-directed ligands (MTDLs). These compounds originated from the combination of different pharmacophoric elements which endowed them with the ability to interfere with different enzymatic and/or receptor systems, or to exert neuroprotective effects by modulating proteins and metal homeostasis. MTDLs have been the focus of the latest strategies to discover a new treatment for Alzheimer’s disease (AD), which is considered the most common form of dementia characterized by neurodegeneration and cognitive dysfunctions. This review is aimed at collecting the latest and most interesting target combinations for the treatment of AD, with a detailed discussion on new agents with favorable in vitro properties and on optimized structures that have already been assessed in vivo in animal models of dementia.

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“…Studies in medicinal chemistry have involved the investigation of heterocyclic scaffolds for the synthesis of potent bioactive compounds [20]. These compounds possess properties that inhibit the proliferation of cancer cells, have anti-microbial properties and have a role in animal models of Alzheimer's disease [21][22][23]. Studies have shown that natural phenolic phytochemicals and synthetic aromatic compounds have biological activities [24].…”

Section: Introductionmentioning

confidence: 99%

Ferulic Acid Induces Apoptosis of HeLa and Caski Cervical Carcinoma Cells by Down-Regulating the Phosphatidylinositol 3-Kinase (PI3K)/Akt Signaling Pathway

et al. 2020

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Departmental sources Background: Ferulic acid is an antioxidant phenolic compound derived from plants, which has effects on cancer cells. This study aimed to investigate the effects of ferulic acid on HeLa and Caski human cervical carcinoma cells and the molecular mechanisms involved. Material/Methods: HeLa and Caski human cervical carcinoma cells were grown in culture and treated with increasing doses of ferulic acid. The MTT assay was used to evaluate cell viability. Flow cytometry was performed with 4',6-diamidino-2-phenylindole (DAPI) and Annexin V staining for cell apoptosis. The expression of myeloid leukemia cell differentiation-1 (Mcl-1) protein and MCL-1 mRNA were determined by Western blot and reverse transcriptionpolymerase chain reaction (RT-PCR). Results: Ferulic acid significantly reduced HeLa and Caski cell viability in the concentration range of 4-20 µM (P<0.05). Ferulic acid treatment promoted DNA condensation and significantly increased apoptosis in Caski cells (P<0.05). Ferulic acid treatment resulted in the activation of pro-caspase-3, pro-caspase-8, pro-caspase-9, and PARP. The MTT assay showed that ferulic acid did not reduce the viability of Caski cells treated with the caspase inhibitor, z-VAD-fmk. Ferulic acid reduced the levels of Bcl-2 and Mcl-1, and increased the levels of Bax and reactive oxygen species (ROS). In Caski cells, Akt and PI3K phosphorylation were reduced by ferulic acid in a concentration-dependent manner. Conclusions: The effects of ferulic acid were dose-dependent and resulted in cell cytotoxicity and apoptosis of HeLa and Caski cells, and the PI3K/Akt signaling pathway was down-regulated in Caski cells.

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Discovery of novel propargylamine-modified 4-aminoalkyl imidazole substituted pyrimidinylthiourea derivatives as multifunctional agents for the treatment of Alzheimer's disease

Cited by 60 publications

References 51 publications

Treatment of Alzheimer's disease with framework nucleic acids

Treatment of Alzheimer's disease with framework nucleic acids

Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

Ferulic Acid Induces Apoptosis of HeLa and Caski Cervical Carcinoma Cells by Down-Regulating the Phosphatidylinositol 3-Kinase (PI3K)/Akt Signaling Pathway

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