The increasing resistance of bacteria to antibiotics poses an ever more acute challenge for the global healthcare system, as many previously treatable infections are becoming less and less curable or even uncontrollable. The World Health Organization (WHO) has classified bacterial resistance to antibiotics as one of the three greatest threats to public health in the 21st century. Therefore, the development of new antimicrobial drugs has become a top priority as it is the only way to prevent this problem from escalating.
Peptidoglycan is an important component of the bacterial cell wall that is synthesized in three different parts of the cell: in the cytoplasm, in the cell membrane and outside the cell. The first stage of the reaction pathway takes place in the cytoplasm, where the enzyme MurA catalyzes an important step. Most current antibacterial drugs inhibit the synthesis of peptidoglycan in the final stages of synthesis, which take place outside the cell. However, some antibiotics act inside the cell, including fosfomycin, which inhibits the activity of the MurA enzyme in the cytoplasm.
This master thesis focuses on the development of glucosamine derivatives through molecular modeling and simulation of natural substrates. For the proper targeting of functional groups and the production of reversible inhibitors, we have chosen the glucosamine skeleton as a base that can penetrate the cell wall and membrane of bacteria and reach the MurA enzyme in their internal environment.Our main goal was to develop a synthetic route for the production of potential inhibitors of the MurA enzyme modified with fragments at the C-6 and N-1 positions. We focused on the use of a new protecting group, BDA, introduced at positions C-3 and C-4. Before introducing BDA, we protected the amine with a Cbz protecting group. We then tried to optimize the conditions and ratio of reagents for the introduction of BDA. When the synthesis did not progress in the next step, we decided to abandon BDA and revert to synthesis via the established protecting groups (trityl at C-6, benzyl at C-3 and C-4). Finally, we attached chloroethyl acetate or bromomethyl acetate to the C-6 position. During this synthesis pathway, we focused on the advantages, disadvantages and challenges we encountered.
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