Beta-lactamases represent an important part of bacterial resistance to β-lactam antibiotics. With their own mechanism of action they open the β-lactam ring needed for antibiotic activity. For the purpose of preventing bacterial resistance three β-lactamase inhibitors are in clinical use (clavulanic acid, sulbactam, tazobactam), used in combination with classic β-lactam antibiotics. Because of their similar mechanism of action, mutations that result in modification of their target sites may lead to cross resistance to all three compounds in bacteria.
That is why in this master's thesis we concentrate on the synthesis of novel penicillin binding protein and/or beta lactamase inhibitors with different structure and mechanism of action. We focused on the synthesis of monobactams with an oxyltosylate group bound to nitrogen and substitution of different sulfur compounds at the 4-β-lactam ring. The mechanism of action of N-tosyloxy-2-azetidines is derived from the ability of the sulfonyloxy group to act as an electron-withdrawing group.
3-butenoic acid was used as a starting compound for our synthesis. In the first step it was converted to acyl chloride and then to hydroxamic acid. In the next step we protected the free hydroxylic group with benzyl chloroformate, which enabled successful cyclization to β-lactam ring. Cyclization was followed by removal of the benzyl carbamate protection group and the introduction of allyl moiety to this site. On this compound we attached four different sulfur compounds which replaced the bromine atom. Final compounds were obtained in two steps by the replacement of allyl with tosyl group.
We successfully synthesized all four desired compounds. Their identity and purity were confirmed by high- resolution mass spectrometry, IR spectroscopy and nuclear magnetic resonance.
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