Design and synthesis of 3-vinylpyridine inhibitors of Mur ligases

Odpornost bakterij na protibakterijske učinkovine postaja svetovni zdravstveni problem. Največji razlog predstavljata neustrezna in prekomerna uporaba teh učinkovin. Potrebe po razvoju novih protibakterijskih učinkovin so sedaj večje kot kadarkoli. Zanimivo tarčo za razvoj novih zaviralcev infekcijskih bolezni predstavlja biosintezna pot peptidoglikana, ki omogoča selektivno delovanje teh učinkovin. Ligaze Mur, ki sodelujejo pri biosintezi peptidoglikana, so zaradi znanega mehanizma in znane kristalne strukture trenutno med najbolj raziskovanimi področij. V sklopu raziskovalnega dela magistrske naloge smo sintetizirali derivate 3-vinilpiridina, potencialne zaviralce encimov ligaz Mur. Osnovo za načrt dela je predstavljal kinazni zaviralec, zadetek, ki smo ga dobili z rešetanjem knjižnice spojin podjetja GSK. Pri sinteznih postopkih smo se posluževali reakcijskih mehanizmov sklopitvenih reakcij ter reakcij pripajanja, s katerimi smo želeli povečati tvorbo interakcij spojin z aktivnim mestom, povečati njihovo topnost ter preveriti vpliv posameznih funkcionalnih skupin na zaviralno delovanje spojin. Biokemijska testiranja, opravljena ob koncu raziskovalnega dela, nakazujejo, da sintetizirane spojine predstavljajo dobro osnovo za nadaljnji razvoj in optimizacijo na področju potencialnih zaviralcev encimov ligaz Mur.Due to the inadequate and overuse of antibiotics, the bacteria began to develop different mechanisms of resistance. Bacterial resistance in now becoming a worldwide health problem. Therefore, there is an urgent need for the new development of antibacterial agents. Because of the possibility of achieving selective toxicity, the peptidoglycan biosynthesis pathway represents an interesting target in the field of the new antibacterial drug development. Mur ligases, which participate in the biosynthesis of peptidoglycan, are thus to their known crystalline structures and working mechanisms currently among the most studied fields. As part of the master thesis we synthesized 3-vinylpyridine derivates, potential inhibitors of Mur ligases. Kinase inhibitor, obtained by the virtual screening, represented the basis for the optimization of chemical compounds. With different coupling reactions we tried to enhance the interactions of compounds with the active site of an enzyme, increase their solubility and check the effect of different functional groups on the inhibitory action of the compound. The biochemical tests performed at the end of the research work indicate that the synthesized compounds provide a good basis for further development and optimization in the field of potential inhibitors of Mur ligases