Sinteza imidazolnih in tiazolnih zaviralcev monoamin oksidaze B

Mikolič, Andrej (author), Frlan, Rok (mentor)

Encim monoamin oksidaza (MAO) ima ključno vlogo pri presnovi monoaminskih nevrotransmiterjev kot so dopamin, noradrenalin in serotonin. Pojavljata se dve izoobliki encima, MAO-A in MAO-B, ki imata zaradi strukturnih razlik in različnega izražanja v specifičnih tkivih različno substratno specifičnost. S selektivnim zaviranjem MAO-B lahko zmanjšamo razgradnjo dopamina, kar poveča njegove učinke v možganih, zato se zaviralci MAO-B uporabljajo pri zdravljenju nevrodegenerativnih bolezni, predvsem Parkinsonove bolezni (PB). Čeprav temelj zdravljenja PB predstavlja levodopa, se v začetnih stadijih bolezni vse pogosteje uporabljajo zaviralci MAO-B, tudi zaradi blažjih neželenih učinkov. Pri raziskovalnem delu v okviru magistrske naloge smo se ukvarjali z načrtovanjem, sintezo in karakterizacijo novih tipov imidazolnih in tiazolnih zaviralcev MAO-B. Vse sintetizirane končne in tudi vmesne spojine smo biokemijsko testirali na rekombinantnih encimih MAO-A in MAO-B. Načrtovanje je potekalo na podlagi ugotovitev predhodnih raziskav, pri čemer smo želeli sintetizirati in preizkusiti zaviralce, ki namesto NO2 skupine in dvojne vezi med aromatskima obročema vsebujejo imidazol ali tiazol kot protonski akceptor. Kot izhodna reagenta smo uporabili 2-bromotiazol oz. 4-bromo-1H-imidazol. Sintezo smo v veliki meri izvajali v mikrovalovnem reaktorju, ki omogoča hitro in učinkovito izvedbo reakcij. Z in vitro encimskim testiranjem smo najvišjo zaviralno aktivnost ugotovili pri tiazol vsebujoči spojini 4 (IC50= 0,207 μM) in imidazol vsebujoči spojini 10 (IC50=4,59 μM). Prav vse sintetizirane spojine, z izjemo spojine 9, so bolje zavirale izoobliko MAO-B. Aktivnosti zaviralcev na izoobliki MAO-A so bile izjemno nizke, vrednosti IC50 v teh primerih niti nismo določali. Ugotovitve te magistrske naloge vsekakor prispevajo k boljšemu poznavanju sinteze imidazolnih in tiazolnih tipov zaviralcev MAO-B, potrjena pa je tudi njihova farmakološka aktivnost. Obstaja torej potencial v smeri razvoja omenjenih spojin, vendar pa je do razvoja in terapevtske uporabe novega učinkovitega in selektivnega zaviralca MAO-B še dolga pot.

• Language: Slovenian
• Keywords: Encimsko testiranje, imidazolni derivati, MAO-B zaviralci, monoamin oksidaze, Parkinsonova bolezen, reakcija Suzuki-Miyaura, tiazolni derivati
• Work type: Master's thesis/paper
• Typology: 2.09 - Master's Thesis
• Organization: FFA - Faculty of Pharmacy
• Publisher: [A. Mikolič]
• Year: 2026
• PID: 20.500.12556/RUL-183092
• UDC: 615.4:54:616.858(043.2)
• COBISS.SI-ID: 280563459
• Publication date in RUL: 04.06.2026

Secondary language

• Language: English
• Title: Synthesis of imidazole and thiazole-based monoamine oxidase B inhibitors

Abstract

Monoamine oxidases (MAO) play a key role in the metabolism of neurotransmitters such as dopamine, noradrenaline and serotonin. Two isoforms of the enzyme exist, MAO-A and MAO-B, which differ in structure and in their expression in specific tissue types, resulting in different substrate specificities. Selective inhibition of MAO-B reduce dopamine degradation and that increases its effects in the brain. Therefore, MAO-B inhibitors are used in the treatment of neurodegenerative diseases, especially Parkinson's disease (PD). Although the primary method of PD treatment is levodopa, MAO-B inhibitors are increasingly used in the early stages of the disease, also due to the milder side effects. In this research, we focused on the design, synthesis and characterization of new types of imidazole and thiazole-based MAO-B inhibitors. All synthesized products (final and intermediate compounds) were biochemically tested on recombinant MAO-A and MAO-B enzymes. The design was based on findings from previous studies. Our aim was to synthesize and evaluate inhibitors that contain imidazole or a thiazole ring as a proton acceptor instead of the NO2 group and the double bond between the aromatic rings. As starting reagents, we used 2-bromothiazole and 4-bromo-1H-imidazole. Most of the synthesis was carried out using a microwave reactor, which enables fast and efficient reactions. In vitro enzymatic testing revealed the highest inhibitory activity for the thiazole-based compound 4 (IC50= 0.207 μM) and the imidazole-based compound 10 (IC50=4.59 μM). All synthesized compounds, with the exception of compound 9, showed stronger inhibition of the MAO-B isoform. The inhibitions of the MAO-A isoform were extremely low, the IC50 values were not determined. The findings of this thesis undoubtedly contribute to a better understanding of the synthesis of imidazole and thiazole-based types of MAO-B inhibitors, and their pharmacological activity has also been confirmed. There is therefore potential for further development of these compounds, although the path toward the development and therapeutic use of a new effective and selective MAO-B inhibitor remains long.

• Keywords: Enzymatic testing, imidazole derivatives, MAO-B inhibitors, monoamine oxidases, Parkinson's disease, Suzuki-Miyaura reaction, thiazole derivatives