The current number of drugs available for the treatment of Alzheimer’s disease (AD) is strongly limited and their benefit for therapy is given only in the early state of the disease. An effective therapy should affect those processes which mainly contribute to the neuronal decay. There have been many approaches for a reduction of toxic Aβ peptides which mostly failed to halt cognitive deterioration in patients. The formation of neurofibrillary tangles (NFT) and its precursor tau oligomers have been suggested as main cause of neuronal degeneration because of a direct correlation of their density to the degree of dementia. Reducing of tau aggregation may be a viable approach for the treatment of AD. NFT consist of hyperphosphorylated tau protein and tau hyperphosphorylation reduces microtubule binding. Several protein kinases are discussed to be involved in tau hyperphosphorylation. We developed novel inhibitors of three protein kinases (gsk-3β, cdk5, and cdk1) and discussed their activity in relation to tau phosphorylation and on tau–tau interaction as a nucleation stage of a tau aggregation in cells. Strongest effects were observed for those inhibitors with effects on all the three kinases with emphasis on gsk-3β in nanomolar ranges.
Background:
Alzheimer´s disease (AD) is characterized by a progressive neuronal degeneration caused by two pathological hallmarks, hyperphosphorylated tau protein aggregated into tau
filaments and amyloid precursor protein derived beta amyloid peptides aggregated into extracellular
amyloid plaques. All attempts so far to find effective drugs failed in clinical trials. AD is a multifactorial disease, so that selective drugs to target one AD-relevant structure alone may not be sufficient.
Objective:
We built novel furopyridines with various substitution patterns to evaluate them as protein
kinases inhibitors of enzymes related to tau pathology.
Method:
Furopyridine derivatives were synthesized and purified using column chromatography. The
protein kinase inhibitory properties were determined in ATP-competition assays with determined
affinity constants for the most active compounds.
Results:
The compounds were prepared in simple two-component reactions of substituted 1,4-
dihydropyridines and respective quinones to obtain various substitutions of the molecular furopyridine scaffold. The substituent effects on the determined kinase inhibitory properties of cdk1,
cdk2, Fyn, JNK3 and gsk-3β are discussed.
Conclusion:
Various 3-substitutions were found most sensitive for the protein kinase inhibition depending on the length, nature and a substituent positioning within. We identified compounds as inhibitors of several kinases as a tool to potentially combat the disease progress in a multitargeting
approach.
Background: Resistance developments against established antibiotics are an emerging problem for antibacterial therapies. Novel antibiotics are urgently needed. Materials & methods: We developed novel small-molecule antibacterials which are easily accessible in a simple one-pot synthesis. The central cyclopentaindole core is substituted with two indole residues. Various indole and cyclopentane substituents have been introduced. Additionally, first indole substituted propene compounds as ring-open variants of the cyclopentaindoles have been yielded and evaluated as antibacterials against Staphylococcus aureus and Enterococcus strains. Results: Most effective compounds have been those with a bromo cyclopentane and a chloro indole substitution. First lead compounds were identified with promising activities similar to that observed in vitro for last resort antibiotics, so that the novel compounds enriche the pool of perspective small-molecule antibacterial drug candidates.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.