Molecules, Vol. 25, Pages 985: Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer ’s Disease

Molecules, Vol. 25, Pages 985: Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease Molecules doi: 10.3390/molecules25040985 Authors: Chaves Resta Rinaldo Costa Josselin Gwizdala Piemontese Capriati Pereira-Santos Cardoso Santos : A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer’s disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and β–amyloid (Aβ) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of Aβ-induced cell toxicity. In silico calculations of some pharmacoki...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research

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Abstract Alzheimer's disease (AD) has become a major world health problem as the population ages. There is still no available treatment that can stop or reverse the progression of AD. Human amnion epithelial cells (hAECs), an alternative source for stem cells, have shown neuroprotective and neurorestorative potentials when transplanted in vivo. Besides, studies have suggested that stem cell priming with plant-derived bioactive compounds can enhance stem cell proliferation and differentiation and improve the disease-treating capability of stem cells. Verbenalin is an iridoid glucoside found in medicinal herbs of Ve...
Source: Aging - Category: Biomedical Science Authors: Tags: Aging (Albany NY) Source Type: research
Abstract Based on structure analyses of butyrylcholinesterase (BChE), a series of 21 acridone glycosides were designed, synthesized and evaluated in vitro for their BChE and acetylcholinesterase (AChE) inhibitory activities. d-ribose derivative 6f exhibited the greatest inhibitory activity on BChE (IC50 = 6.95 μM), and was the most selective inhibitor of BChE with the IC50 ratio of AChE/BChE was 20.59. d-glucose and d-galactose derivatives 6a and 6b showed inhibitory activities against both AChE and BChE. Moreover, compounds 6a, 6b, 6f and 5t were found nontoxic on SHSY5Y neuroblastoma and HepG2 ...
Source: Carbohydrate Research - Category: Genetics & Stem Cells Authors: Tags: Carbohydr Res Source Type: research
We examined several PSEN1 and PSEN2 mutations of known and unknown pathogenicity. Known mutants increased Aβ42/Aβ40 ratio with varying effect on Aβ40, Aβ42, total Aβ levels and Pen-2 expression, which aligns with previous work on these mutants. Our data on novel PSEN1 V142F, G206 V and G206D mutations suggest that these mutations underlie the reported clinical observations in ADAD patients. We believe our novel cell line will be valuable for the scientific community for reliable validation of presenilin mutations and helpful in defining their pathogenicity to improve and facilitate evaluation of ...
Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research
In conclusion, our results demonstrated that SP possesses neuroprotective effects, suggesting it could represent a target for therapeutic intervention in neuroinflammatory disorders. PMID: 32004548 [PubMed - as supplied by publisher]
Source: Neuropharmacology - Category: Drugs & Pharmacology Authors: Tags: Neuropharmacology Source Type: research
Abstract The ubiquitous proteoglycan, biglycan (BGN) acts as an important modulator, regulating key molecular pathways of metabolism and brain function. Autophagy is documented as a defining feature of neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). In the present study, we found that BGN protected neuronal cells from nitric oxide (NO)-induced cell apoptosis. However, it is still unclear that whether the neuroprotective effect of BGN relates to autophagy. Here, we discovered that an NO donor, sodium nitroprusside (SNP) induced autophagy in human SH-SY5Y neuro...
Source: Biotechnology Letters - Category: Biotechnology Authors: Tags: Biotechnol Lett Source Type: research
In conclusion, STS could protect against Aβ-induced cell damage by modulating Aβ degration and generation. Sodium tanshinone IIA sulfonate could be a promising candidate for AD treatment. PMID: 31989795 [PubMed - as supplied by publisher]
Source: J Cell Mol Med - Category: Molecular Biology Authors: Tags: J Cell Mol Med Source Type: research
CONCLUSION: MiR-340 was down-regulated in AD and educed accumulation of amyloid-βthrough targeting BACE1, suggesting a potential therapeutic target for AD. PMID: 31957613 [PubMed - as supplied by publisher]
Source: Current Neurovascular Research - Category: Neurology Authors: Tags: Curr Neurovasc Res Source Type: research
CONCLUSION: Existing in vitro and in vivo data are promising, and highlight that naturally-occurring autophagy-regulating compounds play an important role for the prevention and treatment of neurodegenerative disorders. PMID: 31914904 [PubMed - as supplied by publisher]
Source: Current Pharmaceutical Design - Category: Drugs & Pharmacology Authors: Tags: Curr Pharm Des Source Type: research
Abstract Thirty ferulic acid-based 1,3,4-oxadiazole molecular hybrids were designed, synthesized, and screened them for multifunctional inhibitory potential against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and beta-secretase-1 (BACE-1). Compound 6j was the most potent inhibitor of AChE (IC50 = 0.068 µM). It also showed equipotent inhibition of BChE and BACE-1 with IC50 values of 0.218 µM and 0.255 µM, respectively. Compound 6k possessed the most significant inhibition of BChE and BACE-1 with IC50 values, 0.163 µM and 0.211 µM, respec...
Source: Bioorganic Chemistry - Category: Chemistry Authors: Tags: Bioorg Chem Source Type: research
This study was undertaken whether A β‐induced changes of SESN2 and SIRT1 protein expression, autophagy marker LC3II and lysosomal enzyme TPP1 affected by atorvastatin (Western blot) and its possible role in Aβ neurotoxicity (ELISA).Key findings/resultsWe showed that SESN2 and LC3II expressions were elevated, whereas SIRT1 and TPP1 expressions were decreased in the A β1 –42‐exposed human neuroblastoma cells (SH‐SY5Y). Co‐administration of atorvastatin with Aβ1 –42 compensates SESN2 increase and recovers SIRT1 decline by reducing oxidative stress, decreasing SESN2 expression and increa...
Source: Journal of Pharmacy and Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Research Paper Source Type: research
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