Antibacterial agents are one of the most important and very commonly used groups of medicines. Their action is directed at targets that are by their structure or mechanism, specific to the bacterial cell. An important target is the bacterial cell wall or more specifically its component, peptidoglycan. Most antibacterial agents, whose action is aimed at inhibiting cell wall synthesis, act on peptidoglycan biosynthesis by inhibiting enzymes involved in its biosynthesis. The most important enzymes are penicillin binding proteins PBP. These enzymes are a major target of β-lactam antibiotics, as they mimic the structure of a substrate that otherwise binds to the enzyme. After binding, they inhibit the biosynthesis and repair of peptidoglycan, thereby causing cell death. Bacteria are fighting antibiotics by developing a number of mechanisms that prevent the antibiotic from achieving its effect. Due to the rapid spread of bacterial resistance, it is always necessary to look for new active substances that will work efficiently against strains of bacteria that have developed mechanisms of resistance to the known ingredients so far.
The main goal of the work for the master's thesis was to synthesize azetidin-2-one derivatives, which are the targets of PBP enzymes in bacteria. They belong to the group of β-lactam antibiotics, called monobactams, which, because of their structure, are of interest for the synthesis of new derivatives. 3-Butenoic acid was used as the starting compound for synthesis. It was first converted to acid chloride and then by the formation of amide transformed to hydroxamic acid. Free hydroxylic part of the hydroxamic acid group was protected as benzyl hydroxamate using benzyl chloroformate. In the next step, the compound was cyclized using bromine to give a bisubstituted four-membered azetidin-2-one ring. This was followed by deprotection of the hydroxyl moiety and binding of the allyl group, resulting in the compound to which different substituents were successfully introduced at the C4 site. The nitrogen-bound allyl group was then removed and replaced by the tosyl group. In the final step, we bound the azide group to the C3 site and simultaneously removed the tosyl group. We tried to introduce the phenylacetyl group on the reduced azide moiety and the sulfite group on N-hydroxy-β-lactam.
Due to the poor yields of the individual reaction steps, we were unable to synthesize the final substance. We successfully performed ten- or eleven step synthesis, from a total of fourteen stages, and obtained two compounds that differed in the substituent bound at the C4 site of the azetidin-2-one ring.
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