Tuberculosis is an infectious disease caused by bacteria Mycobacterium tuberculosis and it represents a huge health problem as it causes more than million deaths per year. Despite effective standard treatment with peroral chemotheraupetics, some patients are left behind without possible treatment if they get ill with resistant types of disease. Pharmaceutical companies have been developing new chemotheraupetics and one of the possible targets is enzyme InhA. It is involved in the synthesis of mycolic acids, which are long fatty acids found in the cell walls of Mycobacterium tuberculosis and are essential for cell's survival. By inhibition of this enzyme we prevent synthesis of mycolic acids and kill bacterias.
In this master degree we synthesized nine new compounds, which all inhibit enzyme InhA. We have planned their structures based on structure of compound 1, which is a known inhibitor of InhA. Structures of our compounds originate from structure of compound 2, which exhibits about 40 times weaker IC50 than compound 1. Compound 2 is not stable as it has unsubstituted pyrrole in its structure. Our main goal was to achieve stability of compound 2 by binding electron attractive groups on pyrrole ring and we have managed to synthesize 9 stable derivates. Only compound 10 with appended amide moiety possess comparable activity with compound 2 (IC50 = 0.81 µM). When we added small basic groups (methyl and cyclopropyl amide), we got 10 times weaker activities compared to compound 2. By binding aromatic and acidic substituents we synthesized 40 times weaker inhibitors compared to compounds 2 and 10.
We used HPLC to determine purity of our compounds and mass spectrometry to measure their molar masses. We worked with a microscope with heating table to determine melting points and NMR was used to check structures of compounds. For further work we propose chiral switch of compound 10.
|
