20.500.12556/RUL-105448 Uvedba bioizosternih zamenjav za fenilno skupino na mestu 1 pri 1,2,3,4-tetrahidropirolo[1,2-a]pirazinskem tipu zaviralcev InhA magistrska naloga Introduction of bioisosteric replacements of phenyl group at position 1 of the 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine type InhA inhibitors Tuberkuloza je kronična nalezljiva bolezen, za katero vsako leto po vsem svetu na novo zboli približno devet milijonov ljudi. Povzroča jo bacil Mycobacterium tuberculosis, katerega posebnost je kompleksna celična stena. Eden izmed njenih ključnih gradnikov so mikolne kisline. InhA (2-trans-enoil-ACP reduktaza) je encim, ki v sistemu FASII sodeluje pri njihovi sintezi. Najpogosteje uporabljeno zdravilo v boju proti tuberkulozi je Izoniazid (INH), ki deluje kot zaviralec encima InhA. Za njegovo delovanje je ključen encim KatG, ki ga pretvori v aktivno obliko. V zadnjem desetletju se zaradi mutacij gena katG vse pogosteje pojavljajo na INH odporni sevi M. tuberculosis. Nove tarče učinkovitih inhibitorjev so tako neposredni zaviralci encima InhA, ki za svoje delovanje ne potrebujejo predhodne aktivacije z encimom KatG. V okviru magistrske naloge smo želeli sintetizirati pet derivatov, vendar smo le s tremi uspeli izpeljati sintezo do konca in jih testirati na zaviralno delovanje na encim InhA. Naše sintetizirane tri spojine zavirajo delovanje encima InhA v nizkem mikromolarnem območju. Čeprav najboljši zaviralci zavirajo InhA v nanomolarnem območju, te spojine predstavljajo dobro izhodišče za nadaljnjo sintezo in optimizacijo do potencialnih novih antituberkulotikov. Tuberculosis is a chronic infectious disease which affects about nine million people each year around the world. It is caused by Mycobacterium Tuberculosis which is specific for its complex cell wall. One of its key building blocks are mycolic acids. InhA (2-trans-enoyl-ACP reductase) is an enzyme that is involved in the biosynthesis in the FASII system. The most commonly used medicament in the fight against tuberculosis is Isoniazid (INH), which acts as an InhA inhibitor. The key agent that makes Isoniazid effective is the KatG enzyme, which transforms it into an active form. Over the last decade, due to mutations in the katG gene Mycobacterium Tuberculosis resistance to INH has been increasing. New effective inhibitors are direct InhA inhibitors that block the target InhA without requiring bio-activation with the KatG enzyme. In the master thesis, we wanted to synthesize five derivatives, but we managed to completely synthesize only three of them and test them as inhibitors of the InhA. Our three synthesized compounds inhibit the activity of the InhA in the low micromolar range. Although the best inhibitors inhibit InhA is in the nanomolar range, these compounds provide a good starting point for further synthesis and optimization towards potentially new antituberculotics. mikrobakterijska celična stena mikolna kislina zaviralci InhA sinteza spojin true false false [J. Ahej] Slovenski jezik Angleški jezik Magistrsko delo/naloga 2018-11-30 07:09:58 2019-10-12 20:13:41 2025-04-15 09:22:37 0000-00-00 00:00:00 2018 0 Ljubljana 2018 Ljubljana V, 58 f. 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616-002.5-008:615.2(043.3) 4628081 MAG_Ahej_Janja_2018.pdf MAG_Ahej_Janja_2018.pdf 1 6901BDE723ED8B0DF76C14F50D0F6A7E 252bf3074ffbeeabf5c393c7b867a90ee37b8d3b9b074c715d73404cd6194a04 038bfb1e-a1ba-11eb-a523-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=134932 Fakulteta za farmacijo 0 0 0