20.500.12556/RUL-109059 Sinteza 6-substituiranih tetrahidropirolo[1,2-a]pirazinskih zaviralcev encima InhA Synthesis of 6-substituted tetrahydropyrrolo[1,2-a]pyrazine type of InhA inhibitors Tuberkuloza je bakterijska kronična nalezljiva bolezen, ki še vedno predstavlja velik svetovni zdravstveni problem, saj letno povzroča več kot milijon smrti. Čeprav imamo že več let standardno terapijo s peroralnimi kemoterapevtiki, ki je pri večini okuženih učinkovita, se težave pojavijo pri bolnikih z rezistentnimi oblikami bolezni, ki lahko ostanejo povsem brez možnosti zdravljenja. Zato farmacevtska podjetja razvijajo nove kemoterapevtike, ena izmed njihovih tarč je encim InhA. Ta sodeluje pri sintezi gradnikov celične stene (mikolnih kislin) bakterije Mycobacterium tuberculosis, ki povzroča tuberkulozo. Z direktnimi zaviralci delovanja encima zaviramo njihovo sintezo in tako delujemo specifično baktericidno za hitro rastoče mikobakterije oz. bakteriostatično za počasi rastoče. V naši magistrski nalogi smo sintetizirali različne zaviralce encima InhA. Izhajali smo iz strukture spojine 1, ki je znan in opisan zaviralec encima. Spojina vodnica je bila spojina 2, ki ima IC50 vrednosti približno 40 krat šibkejše kot spojina 1. Pri delu smo želeli doseči stabilnost spojine vodnice, ki je zaradi nesubstituiranega pirolnega obroča v strukturi podvržena oksidaciji. Na pirolni obroč smo zato uvedli različne elektron privlačne skupine in uspelo nam je sintetizirati devet zaviralcev encima InhA, ki so stabilni v prisotnosti kisika. Le eden izmed njih (spojina 10), ki ima vezano amidno funkcionalno skupino, se po aktivnosti lahko primerja s spojino vodnico (IC50 = 0,81 µM). Približno 10 krat šibkejše zaviranje encima smo dobili pri spojinah z uvedenimi majhnimi bazičnimi funkcionalnimi skupinami (metilni in ciklopropilni amid). Z uvajanjem večjih ali kislih funkcionalnih skupin se zaviranje spojin še bolj zmanjša (približno 40 krat). V analiznem delu smo ovrednotili čistočo sintetiziranih spojin z reverznofazno kromatografijo (HPLC), določili njihovo maso z masno spektrometrijo in temperaturo tališč pod mikroskopom z grelno mizico ter posneli NMR spektre spojin. Za nadaljnje delo predlagamo izvedbo kiralne ločbe spojine 10. Tuberculosis is an infectious disease caused by bacteria Mycobacterium tuberculosis and it represents a huge health problem as it causes more than million deaths per year. Despite effective standard treatment with peroral chemotheraupetics, some patients are left behind without possible treatment if they get ill with resistant types of disease. Pharmaceutical companies have been developing new chemotheraupetics and one of the possible targets is enzyme InhA. It is involved in the synthesis of mycolic acids, which are long fatty acids found in the cell walls of Mycobacterium tuberculosis and are essential for cell's survival. By inhibition of this enzyme we prevent synthesis of mycolic acids and kill bacterias. In this master degree we synthesized nine new compounds, which all inhibit enzyme InhA. We have planned their structures based on structure of compound 1, which is a known inhibitor of InhA. Structures of our compounds originate from structure of compound 2, which exhibits about 40 times weaker IC50 than compound 1. Compound 2 is not stable as it has unsubstituted pyrrole in its structure. Our main goal was to achieve stability of compound 2 by binding electron attractive groups on pyrrole ring and we have managed to synthesize 9 stable derivates. Only compound 10 with appended amide moiety possess comparable activity with compound 2 (IC50 = 0.81 µM). When we added small basic groups (methyl and cyclopropyl amide), we got 10 times weaker activities compared to compound 2. By binding aromatic and acidic substituents we synthesized 40 times weaker inhibitors compared to compounds 2 and 10. We used HPLC to determine purity of our compounds and mass spectrometry to measure their molar masses. We worked with a microscope with heating table to determine melting points and NMR was used to check structures of compounds. For further work we propose chiral switch of compound 10. tuberkuloza direktni zaviralci InhA oksidacija pirola HPLC tuberculosis enzyme inhibitors of InhA oxidation of pyrrole HPLC true false false Slovenski jezik Angleški jezik Magistrsko delo/naloga 2019-08-20 08:35:09 2019-08-20 08:35:17 2022-08-21 03:39:42 0000-00-00 00:00:00 2019 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 1970-01-01 68221 432.pdf 432.pdf 1 D5F8AA02E34EC73FD10D041FFAFDFEED 9ddfbd3e5c76405f76bdf98e69993ef8be4134a1aaba8ec8216db15d559a741f c3d64ff2-a1b6-11eb-a523-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=120450 Fakulteta za farmacijo 0 0 0