@misc{Góral_Izabella_Novel_2025,
 author={Góral, Izabella},
 address={Kraków},
 howpublished={online},
 year={2025},
 school={Rada Dyscypliny Nauki farmaceutyczne},
 language={eng},
 abstract={Alzheimer's disease is the most common form of dementia and one of the leading causes of death according to the World Health Organization. The disease's etiopathogenesis is elusive, indicating the aggregates of β- amyloid peptide and tau protein, along with a chronic inflammatory process within nervous tissue as pivotal in driving neurodegeneration. Given the increasing prevalence of Alzheimer's disease and the limited therapeutic efficacy of currently available drugs, AD arises as a significant social, medical, and economic challenge. This doctoral dissertation presents research on a novel class of multifunctional compounds, focused on the search for causal treatment of Alzheimer's disease. The aim of the research presented in this doctoral dissertation was the synthesis and biological evaluation of novel kinase inhibitors characterized as multifunctional ligands, targeting both GSK-3β and IKK-β simultaneously. Such compounds may significantly impact processes associated with Alzheimer's disease development, including abnormal protein aggregation (especially tau protein) and neuroinflammatory processes, thereby potentially modifying disease progression. To achieve the stated objective, four series of novel compounds with potential dual activity were designed and subsequently synthesized. Their structure and purity were confirmed through spectroscopic (NMR) and chromatographic},
 abstract={(LC- MS) methods. Subsequently, all compounds were evaluated for their inhibitory activity against GSK-3β and IKK-β kinases in vitro. The results allowed for initial conclusions to be drawn regarding structure-activity relationships and the selection of the most promising candidates for further in cellulo studies and preliminary ADME profile assessment in vitro. To expand knowledge about the interaction of compounds within the active site of GSK-3β and IKK-β kinases, molecular modeling studies were conducted. Additionally, all final compounds were subjected to in silica analysis of the physicochemical parameters, supplementing the drug-likeness evaluation. The most significant achievement presented in the dissertation is the identification of dual inhibitors of GSK- 3β and IKK-β kinases among the synthesized derivatives. Special attention should be given to compounds 40 and 60, which exhibit stronger inhibition of GSK-3β than IKK-β, as well as to compound 70, which demonstrates the highest balanced inhibitory activity. Additionally, the research identified a group of selective GSK-3β inhibitors with high inhibitory potency, among which compound 62 proved to be the most promising. In cellulo studies confirmed their neuroprotective properties in the okadaic acid-induced hyperphosphorylation assay in the HT-22 cell line. These compounds also exhibited significant activity in a lip},
 abstract={opolysaccharide-induced inflammation model in the BV-2 cell line, reducing the secretion of inflammatory markers such as nitric oxide (IMO), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). In summary, the described research presents selective GSK-3β kinase inhibitors and the first dual GSK-3β/IKK-β ligands with a desired multitarget activity. This unique combination represents an innovative direction in the search for disease-modifying therapies for Alzheimer's disease. Moreover, the presented results provide a solid foundation for further optimization of this group of inhibitors.},
 title={Novel dual inhibitors of GSK-3β i IKK-β kinases : synthesis and structure-activity relationship studises},
 type={Praca doktorska},
 keywords={Alzheimer's disease, GSK-3P, IKK-P, dual inhibitors, structure-activity relationship, neuroprotective properties, anti-inflammatory activity},
}