Infectious diseases pose a major health problem, that has increased with the spread of resistance. For this reason, numerous measures to improve the treatment of infections have been accepted as well as the more sensible use of chemotherapeutic agents and the production of new drugs with chemotherapeutic effects. Bacteria that are resistant to a particular chemotherapeutic agent will generally be resistant to all agents from this group. Within the scope of a master thesis we have tried to synthesise new inhibitors of the D-alanil-D-alanine ligase, i.e. the intracellular bacterial enzyme required for the synthesis of the bacterial cell wall.
We intended to synthesise compounds, which would be analogues of known inhibitors and which would retain the inhibitory activity on the enzyme, but be permeable to the cell membrane and had proper pharmacokinetic properties that known inhibitors normally do not have and is probably the reason for the lack of their clinical use. Basic building block of our compounds was N-(2-aminoethyl)-2,4-dihidroxybenzamide, with different bound fragments in place 2.
We prepared two basic reagents to which we attached different fragments, first reagent methyl 4-(benzyloxy)-2-hidroxybenzoate turned out to be quite unreactive, the second benzyl (2-(4-(benzyloxy)-2-hidroxybenzamido)ethyl)carbamate as a slightly more reactive, but it was usually needed to use aggressive conditions for successful synthesis, such as high temperature and addition of larger amounts of reagents.
We synthesised series of products, due to time constraints some products were synthesised in amounts, that allowed only chemical analysis of the product and confirmations of synthesis, but not biological evaluation.
We prepared a synthetic pathway that could be used for synthesis of such compounds. We suggested the alternative synthesis route in some cases, where planned reactions did not yield the desired product.
|
