ABSTRACT
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 Aß 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-3ß, cdk5, and cdk1) and discussed their activity in relation to tau phosphorylation and on tauâ»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-3ß in nanomolar ranges.
Subject(s)
Benzofurans/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Pyridines/chemical synthesis , tau Proteins/metabolism , Animals , Benzofurans/chemistry , Benzofurans/pharmacology , CDC2 Protein Kinase/metabolism , COS Cells , Cell Line , Chlorocebus aethiops , Cyclin-Dependent Kinase 4/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Phosphorylation/drug effects , Protein Aggregates/drug effects , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Sf9 Cells , tau Proteins/chemistryABSTRACT
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.