Antibacterial agents are very important group of drugs since infectious diseases represent the second leading cause of mortality in the world. They are used for the treatment of various bacterial infections (e.g. pneumonia, skin infections, eye infections, GI tract infections, sexually transmitted diseases). The main problem of antibacterial agents is the development of resistance of various bacterial strains to them. We struggle against this with the discovery of new molecules which bind to specific binding sites of biological targets or have different mechanisms of inhibition. In the master thesis we synthesized potential gyrase B inhibitors, which is well established and validated target for developing new antibacterial agents. We started from lead compound oroidin that was isolated in 1971 from sponges Algeas oridides. In our compounds we kept the bromopyrrole ring, but we replaced the alkyl chain with 1,4-benzoxazine scafffold. The first step in the synthesis was the reduction of the ethyl esters of 1,4-benzoxazine carboxylic acids and then the attachment of dibromopyrrole carboxylic acid using TBTU as reagent for activating carboxylic acid. Thus we obtained the ethyl esters that were converted by basic hydrolysis to carboxylic acids – our final compounds. We also synthesized the methylated and the dimethylated analogue. Finally, we tried to synthesise the analogue with a longer oxalate chain, but we were not able to obtain the final compound because in the last stage of the reaction by-products were formed. We confirmed the structure and purity of the prepared compounds by spectroscopic methods and by determining the melting point interval. Compounds were tested for inhibition of gyrase and the most active compound was the 7- (4,5-dibromo-1H-pyrrole-2-carboxamide)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-carboxylic acid with an IC50 of 36,3 μM. All other prepared compounds were weakly active with an IC50 > 100 μM or inactive.
|
