Design, příprava a hodnocení malých molekul pro neurodegenerativní onemocnění

Mgr. Žofia Chrienová

Doctoral thesis

Design, synthesis, and evaluation of small molecules for neurodegenerative diseases

Abstract:

Alzheimer's disease is one of the most prevalent neurodegenerative disorders among the world’s aging population. The presented dissertation depicts the design, preparation, and evaluation of small molecules targeting Alzheimer’s disease pathogenesis as described in two etiological hypotheses.Addressing the well-known cholinergic hypothesis of Alzheimer’s disease, the multi-target-directed ligand strategy was utilized to develop three series of tacrine derivatives as disease-modifying agents. Prepared structures combined the inhibition of cholinesterases with the inhibition of glutamate excitotoxicity, amyloid-β aggregation, or monoamine oxidases.The literature review summarized in the theoretical part of this thesis describes the objective of our recent studies that focus on the inhibition of the mammalian target of rapamycin. This biological target was selected for its potential role in age-related disease development, including Alzheimer’s disease. Agents modifying dysregulated signaling pathways in aging cells might possess the cause-treating capacity in Alzheimer’s disease, according to the aging hypothesis. Thus, the series of novel and repurposed molecules were evaluated for their senolytic and senomorphic properties.The lack of therapeutic options for Alzheimer’s disease patients determines the continuous endeavor in drug development. Molecules addressing different approaches that were prepared and evaluated in this thesis might provide novel insight into the effort of disease-modifying and causative Alzheimer’s disease therapy discovery.

Keywords

Alzehimer's disease, age-related diseases, mTOR, MTDL, senolytics, senomorphics

Language used: English

Date on which the thesis was submitted / produced: 20. 11. 2023

Thesis defence

• Date of defence: 23. 1. 2024
• Supervisor: prof. Ing. Kamil Kuča, Ph.D.
• Reader: Zdeněk Heger, Mária Kožurková

University of Hradec Králové

Faculty of Science

Doctoral programme / field:
Toxikologie / Toxikologie