Načrtovanje in sinteza substituiranih 2-oksoazetidin-1-sulfonatov kot zaviralcev β-laktamaze

Prašnikar, Eva (author), Obreza, Aleš (mentor)

Betalaktamski antibiotiki so najpogosteje uporabljana skupina antibiotikov za zdravljenje bakterijskih infekcij, vendar je problematičen pojav odpornosti nanje. Najpomembnejši mehanizem bakterijske odpornosti je njihova sposobnost sinteze encimov betalaktamaz, ki katalizirajo hidrolizo betalaktamov do neaktivnih produktov. Ker se bakterijska odpornost na antibiotike iz leta v leto povečuje, postajajo možnosti za zdravljenje okužb vse bolj omejene. Zato je ključnega pomena odkrivanje novih protimikrobnih učinkovin in učinkovin, s katerimi bi lahko premostili omenjene mehanizme odpornosti. Monociklični betalaktami so dokazano slabši substrati za betalaktamaze in v nekaterih primerih so na njih delovali zaviralno. Ti dve lastnosti sta pri reševanju problematike z betalaktamazami posredovane bakterijske odpornosti zaželeni, zato so omenjene molekule zanimive za načrtovanje novih zdravilnih učinkovin. Odločili smo se, da bomo v okviru naše magistrske naloge poskusili sintetizirati nove predstavnike te skupine betalaktamskih antibiotikov. Pripravili smo 2-oksoazetidin-1-il-sulfonate z žveplovim substituentom na C4 mestu betalaktamskega obroča. Najprej smo s pomočjo oksidativne ciklizacije ?,?-nenasičenega O-acil hidroksamata, sintetizirali osnovni betalaktamski obroč. Tu smo se srečali z izjemno nizkimi izkoristki, zato smo poskušali optimizirati najbolj težavno, tretjo sintezno stopnjo. Pred uvedbo žveplo vsebujočega substituenta na C4 mesto, je bila za stabilnost produkta nujna zamenjava zaščitne skupine na 1N-OH položaju. Na C4 mesto smo uvedli tri tiole (tiazol-2-tiol, 1-metil-1H-imidazol-2-tiol in 1H-1,2,4-triazol-3-tiol). Na koncu je sledila še ponovna zamenjava skupine na 1N-OH mestu, kamor smo vezali tosilno skupino. Uspelo nam je sintetizirati en končni produkt 2-oksoazetidin-1-il-sulfonatov (2-okso-4-((tiazol-2-iltio)metil)azetidin-1-il 4-metilbenzensulfonat). V ostalih dveh primerih smo sintezo zaključili v sedmi sintezni stopnji. Identiteto izoliranih produktov smo preverili z jedrsko magnetno resonanco (1H in 13C), masno spektrometrijo visoke ločljivosti, masno spektrometrijo, IR spektrometrijo in v primeru trdnih spojin tudi z določitvijo talilnega intervala.

• Language: Slovenian
• Keywords: Betalaktamski antibiotiki, monociklični betalaktamski antibiotiki, bakterijska odpornost, betalaktamaze, 2-oksoazetidin-1-il sulfonati
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2019
• PID: 20.500.12556/RUL-109327
• Publication date in RUL: 30.08.2019

Secondary language

• Language: English
• Title: Design and synthesis of substituted 2-oxoazetidine-1-sulfonates as β-lactamase inhibitors

Abstract

Beta lactam antibiotics are the most commonly used family of antibacterial compounds. Nowadays we are facing an acute problem of bacterial resistance to them, the most common and problematic mechanism being their new-found ability to produce beta lactamases. Beta lactamases are enzymes which catalyse the hydrolysis of beta lactam antibiotic and render them inactive. Because bacterial resistance to antibiotics is growing every year, the possibilities for treatment of bacterial infections are getting more and more limited. Therefore the discovery of new antimicrobial drugs and substances which could overcome mentioned mechanisms of resistance are of key importance. Monocyclic beta lactams are poor substrates for beta lactamases and have in some cases even shown to have beta lactamase inhibitory properties. These two qualities are desirable in solving the problem of beta lactamases mediated resistance. Therefore monocyclic beta lactams represent an interesting field of investigation in pharmacy and we decided that in our thesis we will try to synthetize some new representatives of antibacetrially active monocyclic beta lactams. We have synthetized 2-oxoazetidine-1-yl-sulfonates with thiol substituents on C4 position of beta lactam ring. With the help of oxidative cyclization of ?,?-unsaturated O-acyl hydroxamate, we first synthetized substituted beta lactam ring. Here we found ourselves with extremely low yields and have tried to optimize the most problematic, third stage of the synthesis. Before the introduction of thiol substituent on C4 position of beta lactam ring, we had to change the protection group on 1N-OH position of beta lactam ring in order to obtain a proper stability of appropriately C4 substituted products. On C4 position we have introduced three thiol substituents (thiazole-2-thiol, 1-methyl-1H-imidazole-2-thiol, 1H-1,2,4-triazole-3-thiol). In the end we changed the 1N-OH moiety, introducing tosyl group. We managed to prepare one representative of 2-oksoazetidin-1-ilsulfonates (2-oxo-4-((thiazol-2-ylthio)methyl)azetidin-1-yl 4-methylbenzenesulfonate). In other two cases the synthesis stopped at the seventh reaction stage. We have confirmed the identity of the final compounds with nuclear magnetic resonance (1H in 13C), high resolution mass spectrometry, mass spectrometry, IR spectroscopy and in case of solid compounds we also measured the melting points.

• Keywords: Beta lactam antibiotics, monocyclic beta lactam antibiotics, bacterial resistance, beta lactamases, 2-oxoazetidine-1-yl-sulfonates