Monoamine oxidases are enzymes located on the outer membrane of mitochondria. They are responsible for the metabolism of substrates containing an amino group. Certain drugs used in the treatment of Parkinson's disease are also metabolized in this way. There are two types of monoamine oxidases: A and B, with type B being more relevant to this thesis.
Parkinson's disease is a common neurodegenerative disorder that typically affects older individuals. It is characterized by the degeneration of dopaminergic neurons in the substantia nigra, leading to a decrease in dopamine levels in the brain. Symptoms of Parkinson's disease include tremor, rigidity, and bradykinesia. Current treatments are symptomatic and do not prevent disease progression.
In this thesis, we focused on the synthesis of (E)-3-(4-methoxystyryl)pyridine derivatives as potential selective MAO-B inhibitors. The model compound was selected from research conducted at the Faculty of Pharmacy, where the IC50 value for this compound was determined to be 42.2 ± 4.9 nM. Our primary goal was to synthesize derivatives that do not contain a nitro group. Additionally, we planned the synthesis of heterocycles within the structure to enhance activity.
We successfully synthesized four selective MAO-B inhibitors, which were evaluated through biological testing on human MAO-A and -B enzymes. The activity of the compounds was compared with that of the model compound and safinamide, a clinically used reversible MAO-B inhibitor. Based on the obtained data, we found that compounds lacking a nitro group maintained sufficiently high activity and selectivity for MAO-B. It was also found that the heterocycle structure forms significant interactions with the active site. Although none of the compounds exhibited a lower IC50 value than the model compound, our findings indicate that the synthesized compounds are worthy of further research and development.
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