20.500.12556/RUL-184329 Sinteza in vrednotenje zaviralcev InhA s tiosečninsko in fenolno strukturo Synthesis and evaluation of InhA inhibitors with thiourea and phenolic structures Tuberkuloza je veliki javnozdravstveni problem, pri čemer predstavlja razvoj odpornosti na obstoječa zdravila velik izziv za sodobno farmakoterapijo. Ena izmed raziskovanih tarč za razvoj novih zdravilnih učinkovin je tudi encim enoil-ACP-reduktaza (InhA), ki sodeluje v biosintezi mikolnih kislin v celični steni bakterije povzročitelja tuberkuloze, Mycobacterium tuberculosis. Namen magistrske naloge je bil sintetizirati in biokemijsko ovrednotiti nove potencialne zaviralce encima InhA s tiosečninsko in fenolno strukturo. Na podlagi podatkov pridobljenih iz predhodne študije molekulskega sidranja smo sintetizirali nove spojine po večstopenjskih sinteznih poteh. Pri sintezah smo izvedli uvedbo in odstranjevanje zaščitnih skupin, tvorbo amidnih vezi, sintezo tiosečninskih derivatov ter uporabo različnih reakcijskih pogojev kot na primer reakcije v mikrovalovnem reaktorju. Potek reakcij smo spremljali s tankoplastno kromatografijo (TLC), tekočinsko kromatografijo sklopljeno z masno spektrometrijo (LC-MS) in jedrsko magnetno resonanco (NMR). Strukture končnih spojin smo potrdili z uporabo raznolikih analitskih metod. Med sintezo smo naleteli na več izzivov, kot so nizki izkoristki, slaba topnost ter nastajanje stranskih produktov. Kljub temu smo uspeli izolirati in karakterizirati devet spojin, ki smo jih ovrednotili v sklopu biokemijska testiranja in vitro. Biokemijski testi so pokazali, da testirane spojine niso izkazovale pomembne zaviralne aktivnosti na encim InhA, saj je ta ohranil visoko rezidualno aktivnost. Čeprav niso pokazale aktivnosti, lahko prispevajo k boljšemu razumevanju odnosa med strukturo in biološko aktivnostjo. Tako lahko predstavljajo izhodišče za nadaljnjo optimizacijo za razvoj novih, učinkovitejših zaviralcev encima InhA. Tuberculosis is a major public health problem, with the emergence of resistance to existing drugs posing a significant challenge to modern therapy. One of the promising new therapeutic approaches is targeting the enzyme enoyl-ACP-reductase (InhA), which plays an important role in the process of biosynthesis of mycolic acids that are crucial for the cell wall of the Mycobacterium tuberculosis, the causative agent of tuberculosis. The aim of this thesis was the synthesis and biochemical evaluation of new potential InhA enzyme inhibitors with thiourea and phenolic structures. Based on data received from previous molecular docking studies, we synthesised several new compounds through multistep synthetic pathways. In the process we included the introduction and removal of protecting groups, formation of amide bonds, synthesis of thiourea derivatives and the application of different reaction conditions such as microwave-assisted reactions. We monitored the progress using thin-layer chromatography (TLC) along with liquid chromatography coupled with mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) analysis. We confirmed the structure of final products using different analytical methods. During synthesis we faced several challenges, such as low yields, poor solubility and the formation of side products. However, we successfully isolated and characterized nine compounds that underwent biochemical evaluation in vitro. Biological testing showed that the synthesized product did not exhibit significant inhibitory activity against the InhA enzyme, since high residual activity was observed. Despite no activity showed, our results contribute to a better understanding of the structure-activity relationship, providing information for future optimization in the development of new, more effective InhA inhibitors. InhA encim Mycobacterium tuberculosis sinteza učinkovin tuberkuloza zaviralci InhA encima drug synthesis InhA enzyme InhA inhibitors Mycobacterium tuberculosis tuberculosis true false false [M. Mihorko] Slovenski jezik Angleški jezik Magistrsko delo/naloga 2026-07-04 08:45:25 2026-07-04 08:45:35 2026-07-07 15:10:55 0000-00-00 00:00:00 2026 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 1970-01-01 616-002.5(043.2) 125635 283893763 32328.pdf 32328.pdf 1 B6940FC3F718A17A7298E499B16CF837 3d4c36a43e70fa39376495568ddc3124eb74a3fe9aee5f3970950abc1db18d45 d9830c1b-7773-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=237009 Fakulteta za farmacijo 0 0 0