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.