The fight against bacterial infections has been one of the great success stories of 20th century medicine. However, extensive use, and also misuse of antibiotics have caused emergence of antimicrobal-resistant pathogenic bacteria, which now present a serious threat to public health and a need for a constant development of new antibacterial agents. While a large number of antibiotics in clinical use act by inhibiting later steps in peptidoglycan synthesis, the earlier steps of the biosynthesis of cytoplasmic peptidoglycan precursor are poorly exploited as antibacterial targets. Among them, Mur enzymes, as essential part of bacteria, enable design of inhibitors with potencial bactericidal and wide spectrum activity.
In this master’s thesis we synthetized analogues of previously discovered azastilbene compound, that inhibited MurC-F in micromolar range. Via Suzuki coupling, we replaced furan, containing oxygen in ortho position, with various heterocycles; as well we synthetized 2-oxazoline, 2-imidazoline and 2-thiazoline instead of 5-substituted terazole and reduced azastilbene’s double bond.
Synthesized compounds were tested for their inhibitory effect on enzymes MurC, D, E and F from E. coli. Residual activity [%] was measured for each of them, and for the most potential coumpounds, IC50 values [μM] were determined. Comparison of compounds 3a and 4a shows the importance of tetrazole at reaching inhibitory activities on MurD-F, while for MurC inhibition, tetrazole is not the best option. Furan with oxygen in ortho position seems to be essential, as the rest of analogues with other heterocycles in this place, does not show inhibitory activity on any Mur enzyme. Beside the presence of oxygen in furan, its ortho position is also significant, as we are able to see from comparison of compounds 4b and 4f. The best inhibitor was compound 13 that shows inhibitory activity on MurC, D and F, therefore it is classified as multiple inhibitor, which minimize the possibility of resistance development. Only compound 12 achieved significant antibacterial activity on S. aureus with values 10,65 μg/mL.
To conclude, we manage to study the effect of different substituents on MurC-F inhibition, wherein compound 13 represents the basis for further studies of multiple azastilbene inhibitors.