Successful development of antibacterial agents and the effectiveness of treatment of bacterial infections is steadily declining. The main reason is development of bacterial resistance to individual antibacterial agents. There is a wide range of antibacterial drugs in clinical use, nevertheless new drugs with novel mechanisms of action are required. Interesting and promising field for development of new antibacterial are bacterial enzymes involved in the synthesis of the main building block of the cell wall, peptidoglycan. By inhibiting peptidoglycan synthesis, cell death is thus triggered. The main advantage of this mechanism of action is selective toxicity, which means that inhibition occurs only in bacterial cells, as peptidoglycan is not present in the human cell. MurA (UDP-N-acetylglucosamine enolpiruvyl transferase) is an enzyme involved in the first stage of peptidoglycan synthesis. The therapeutically effective drug in clinical use is phosphomycin.
In this master's thesis we synthesized new potential inhibitors of the MurA enzyme. The starting points were 2-aminothiazole derivatives from which we synthesized 2-bromothiazoles. Then we exchanged the bromide atom with the vinyl group and one with an iodine atom. The inhibitory activity of the obtained compounds was determined by using biochemical assays on MurA from Escherichia coli.
Six compounds (2, 5, 7, 11, 16 in 23) showed the most potent inhibitory effect. They inhibited the enzyme in the low micromolar range and the residual activities of the compounds were lower than 50% at a concentration of 500 µM. Compound 23 (IC50 = 70 µM) had the strongest effect, with a vinyl group at position 2 and a carboxyl group at position 4. Compounds 2 (IC50 = 85 µM) and 11 ( IC50 = 141 µM) both with the bromide atom in the position 2 on the thiazole ring were identified as potent inhibitors. Compound 16 (IC50 = 471 µM) with a vinyl group at position 2 also showed promising inhibitory activity.
In conclusion, both the vinyl group and bromide atom were crucial for the inhibitory action of the compound, nevertheless the 2-vinylthiazole derivative (compound 23) proved to be the most potent inhibiotr of MurA. Side groups attached on thiazole showed a large impact on inhibition, which proved that bromothiazoles (2, 5, 7, 11) are good enzyme inhibitors.
Compounds 23 and 2 represent a good starting point for the development of stronger and more selective MurA enzyme inhibitors.