Tuberculosis remains the leading cause of death from infectious disease in adults worldwide. The main agent of tuberculosis is Mycobacterium tuberculosis, which most commonly infects lungs. The first drug discovered for treatment of tuberculosis was isoniazid, which is still used today in combination with other first-line drugs for treatment. Isoniazid targets the enzyme 2-trans-enoyl-ACP reductase (InhA), which is involved in the synthesis of mycolic acids that are important for the survival of mycobacteria. Isoniazid is a prodrug, meaning that its action requires prior activation by the peroxidase enzyme KatG. Recently, however, there have been several strains that are resistant to isoniazid because they contain a mutation in the gene for synthesis of the enzyme KatG, resulting in decreased activity of isoniazid and less effective treatment. Because of this problem, research is now increasingly focused on discovering direct inhibitors of the InhA enzyme. In 2011, GlaxoSmithKline conducted a high-throughput screening of a large number of compounds believed to inhibit the InhA enzyme and discovered a new GSK lead compound from the thiadiazole group. As part of the master's thesis, we first prepared a suitable azide representing the analogue of the left part of the molecule of the lead compound GSK-693. In previous synthesis attempts, the first reaction step did not proceed stereoselectively, but we succeeded in the first attempt, probably because we used the less basic NaHCO3 instead of Na2CO3 during isolation. The remaining steps of the synthesis, the reduction of the ester to an alcohol and the conversion of the alcohol to the azide, proceeded without problems and in satisfactory yields. The synthesised azide was then coupled to various alkynes by copper(I) catalysed Huisgen cycloaddition to potential InhA inhibitors by other graduates. The second part of the master thesis is related to the synthesis of alkynes from various acetophenones with Grignard reagent. In addition to the addition of the Grignard reagent to the acetophenone, the reaction involves a side reaction to syn-1,3-diol, which has not been described so far. In the following, we were first interested in the conditions under which the reaction proceeds best to the above-mentioned sin-1,3-diol. Then, under optimised conditions, we carried out reactions of different acetophenones with acetylene magnesium bromide and determined at which functional groups of the acetophenones the side reaction proceeds preferentially. The results of the analyses indicate that addition proceeds for acetophenones having electron-donor groups on the aromatic ring, whereas syn-1,3-diols are formed in the case where there are electron-acceptor groups on the aromatic ring or the heteroaromatic systems themselves are electron-acceptor.
|
