Sinteza tiazolnih zaviralcev monoamin oksidaze B za zdravljenje Parkinsonove bolezni

Seliškar, Petra (avtor), Frlan, Rok (mentor)

Parkinsonova bolezen (PB) je nevrodegenerativna motnja, ki prizadene milijone ljudi po vsem svetu. Ključno vlogo pri razvoju te bolezni ima pomanjkanje dopamina v možganih, kar povzroča simptome, kot so tresenje, togost in težave z gibanjem. Pri razgradnji dopamina sodeluje encim monoamin oksidaza B (MAO-B), zato je zaviranje njegove aktivnosti učinkovit način za povečanje razpoložljivosti dopamina in lajšanje simptomov PB. Čeprav trenutno obstajajo zdravila, ki lahko znatno lajšajo simptome, pogosto povzročajo stranske učinke in ne upočasnjujejo napredovanja bolezni, kar ustvarja potrebo po novih in izboljšanih terapijah. Cilj te magistrske naloge je sinteza in vrednotenje novih tiazolnih derivatov kot potencialnih zaviralcev MAO-B. Raziskava vključuje dvostopenjsko sintezo tiazolnih derivatov z namenom izboljšanja izkoristka in čistosti produktov s prilagajanjem reakcijskih pogojev. Naše delo je temeljilo na dvostopenjski sintezi iz 2,5-dibromotiazola ali 2,4-dibromotiazola, kjer smo preučevali različne reakcijske pogoje za optimizacijo izkoristkov in čistosti produktov. Sintezo smo izvajali z različnimi katalizatorji, bazami, topili in ligandi, ki smo jih preizkusili v različnih kombinacijah, da bi natančno analizirali vpliv posameznih komponent na potek reakcije. Pri tem smo uporabili različne tehnike, med katerimi se je kot posebej učinkovita izkazala sinteza z uporabo mikrovalov. Mikrovalovno segrevanje je omogočilo hitre, energetsko učinkovite in visoko selektivne reakcije, kar je bistveno pripomoglo k povečanju izkoristkov in čistosti končnih produktov. Ta tehnika je omogočila tudi boljše obvladovanje reakcijskih pogojev. Poleg mikrovalovnega segrevanja smo preučevali tudi druge reakcijske pogoje, kot so različne temperature, reakcijski časi in koncentracije reagentov, da bi pridobili celovit vpogled v optimalne pogoje za sintezo tiazolnih derivatov. V okviru magistrske naloge smo uspešno sintetizirali štiri derivate tiazola z različnimi substituenti. Najboljše rezultate smo dosegli z uporabo 2,4-dibromotiazola kot izhodne spojine. Nekatere sintetizirane spojine so pokazale zaviralno aktivnost za MAO-B z nizkimi vrednostmi IC50, kar kaže na njihov potencial kot terapevtske učinkovine za zdravljenje Parkinsonove bolezni.

• Jezik: Slovenski jezik
• Ključne besede: tiazolni derivati, monoamin oksidaza B, Parkinsonova bolezen, zaviralci encimov, Suzuki- Miyaura reakcija
• Vrsta gradiva: Magistrsko delo/naloga
• Organizacija: FFA - Fakulteta za farmacijo
• Leto izida: 2024
• PID: 20.500.12556/RUL-160259
• Datum objave v RUL: 24.08.2024

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Synthesis of thiazol-based monoamine oxidase B inhibitors for the treatment of Parkinson's disease

Izvleček

Parkinson's disease (PD) is a neurodegenerative disorder that affects millions of people worldwide. A key factor in the development of this disease is the deficiency of dopamine in the brain, which causes symptoms such as tremors, rigidity, and movement difficulties. The enzyme monoamine oxidase B (MAO-B) is involved in the breakdown of dopamine, so inhibiting its activity is an effective way to increase dopamine availability and alleviate the symptoms of PD. Although there are currently medications that can significantly relieve symptoms, they often cause side effects and do not slow the progression of the disease, highlighting the need for new and improved therapies. The aim of this master's is the synthesis and evaluation of new thiazole derivatives as potential MAO-B inhibitors. The research involves a two-step synthesis of thiazole derivatives based on the modification of reaction conditions to improve yield and product purity. Our work was based on the two-step synthesis from the starting compounds 2,5-dibromothiazole and 2,4-dibromothiazole, exploring different reaction conditions to optimize yields and product purity. The synthesis was carried out using various catalysts, bases, solvents, and ligands, which were tested in different combinations. In this way, we precisely analyzed the influence of individual components on the reaction course. Among the various techniques used, microwave synthesis proved to be particularly effective. Microwave heating allowed for rapid, energy-efficient, and highly selective reactions, significantly contributing to increased yields and purity of the final products. This technique also enabled better control of the reaction conditions. In addition to microwave heating, we also examined other reaction conditions such as different temperatures, reaction times, and reagent concentrations, providing a comprehensive insight into the optimal conditions for the synthesis of thiazole derivatives. In the course of this master's thesis, we successfully synthesized four thiazole derivatives with various substituents. The best results were achieved using 2,4-dibromothiazole as the starting compound. Some of the synthesized compounds exhibited inhibitory activity against MAO-B, with low IC50 values, indicating their potential as therapeutic agents for the treatment of Parkinson's disease.

• Ključne besede: thiazole derivatives, monoamine oxidase B, Parkinson's disease, enzyme inhibitors, Suzuki-Miyaura reaction