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Sinteza in vrednotenje 3,4-dikloro-5-metil-N-fenilpirolamidnih zaviralcev DNA-giraze B = The synthesis and evaluation of 3,4-dichloro-5-methyl-N-phenylpyrrolamide inhibitors of DNA gyrase B : enoviti magistrski študijski program FarmacijaKrižaj, NikaOdpornost bakterij proti antibiotikom predstavlja enega večjih svetovnih problemov, saj se rezistenca pojavi kmalu zatem, ko je antibiotik uveden v terapijo. Odkritje novega antibiotika bi ... predstavljalo velik napredek v boju proti bakterijski odpornosti. Ena izmed tarč z dobrim potencialom je DNA-giraza, ki spada v skupino encimov imenovanih topoizomeraze. DNA-giraza je zgrajena iz dveh podenot A in dveh podenot B, ki predstavljata tarči delovanja protibakterijskih učinkovin. V okviru magistrske naloge smo sintetizirali tri zaviralce DNA-giraze B s 3,4-dikloro-5-metil-N-fenilpirolamidnim skeletom. Z namenom tvorbe dodatnih in močnejših interakcij v vezavnem mestu encima, smo na osnovni skelet vezali različne substituente. Z določanjem srednje zaviralne koncentracije (IC50) na DNA-girazi iz Escherichia coli, smo ovrednotili aktivnost sintetiziranih spojin in vpliv različnih substituentov na njihovo vezavo. Sinteza spojin je potekala po treh ločenih sinteznih poteh. Tekom sinteze smo spojinam določili identiteto, fizikalno-kemijske lastnosti in čistost s kromatografskimi (tankoplastna in kolonska kromatografija, tekočinska kromatografija visoke ločljivosti) in spektroskopskimi metodami (jedrska magnetna resonanca, infrardeča spektroskopija, masna spektrometrija) ter merjenjem temperature tališča. Kot najbolj aktivna spojina se je izkazala spojina 20 (IC50 = 243 nM), ostali spojini (12 in 7) sta bili slabše aktivni (IC50 > 1µM). Vzrok za slabšo aktivnost je mogoče pripisati vezavi benzilnega (7) in metoksi etilnega (12) substituenta na dušikov atom amidne skupine, saj ta dva substituenta ne tvorita ugodnih interakcij v t.i. lipofilnih tleh encima. Močnejše delovanje so imele spojine, ki so imele alifatske oz. aromatske substituente vezane neposredno na orto mesto (glede na pirolamidni del) osrednjega fenilnega obroča. Spojina 20, s sulfonamidno skupino na desnem delu molekule, je ohranila del aktivnosti, vendar je bila ta slabša v primerjavi s spojinami, ki imajo na tem mestu vezane kisle heterocikle, npr. 1,3,4-oksadiazol-2-onski obroč ali tetrazol. Čeprav v okviru magistrske naloge nismo uspeli pripraviti spojin z močno zaviralno aktivnostjo na encimu DNA-giraza, smo pridobili informacije, ki bodo uporabne pri načrtovanju novih zaviralcev DNA-giraze B.Type of material - master's thesis ; adult, seriousPublication and manufacture - Ljubljana : [N. Križaj], 2022Language - slovenianCOBISS.SI-ID - 111587075
Author
Križaj, Nika
Other authors
Zidar, Nace
Topics
Bakterijska rezistenca |
DNA-giraza |
zaviralci DNA giraz |
protibakterijska učinkovina |
N-fenilpirolamid |
načrtovanje učinkovin |
optimizacija
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Library/institution |
City | Acronym | For loan | Other holdings |
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Faculty of Pharmacy, Ljubljana | Ljubljana | FFALJ |
reading room 1 cop.
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Križaj, Nika | ![]() |
Zidar, Nace | 28905 |
Source: Personal bibliographies
and: SICRIS
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