Tuberculosis (TB) is a chronic infectious disease caused by different strains of mycobacteria, usually Mycobacterium tuberculosis. The annual incidence is around 10 million, and 1,4 million people die each year from TB itself or its consequences. The disease is still one of the ten most common causes of death in the world population, despite many cures. The current first-line drugs are rifampicin and isoniazid, but the real problem represent strains resistant to these drugs - MDR-TB (multidrug-resistant TB). MDR-TB is a growing challenge because it increases the duration and costs of the treatment. Therefore, we need constant development of newer chemotherapeutic agents targeting new and old target. Among the latter is an enzyme InhA, which is involved in the synthesis of the cell wall (mycolic acids) of M. tuberculosis and is also a target of isoniazid. However, isoniazid must first be activated by peroxidase KatG. If the KatG gene is mutated, isoniazid cannot be activated and becomes ineffective. Due to the increasing emergence of resistance, the research is being focused on the development of direct inhibitors of InhA.
In this master’s degree we synthesized analogues of the thiadiazole inhibitor of the mycobacterial enzyme InhA. The synthesis of the thiadiazole inhibitor is linear and challenging, so we replaced thiadiazole with triazole. This allows easy preparation of analogues by Huisgen alkyne-azide cycloaddition catalyzed by Cu(I) and at the same time retains high structural similarity of proposed compound to the well characterized thiadiazole type inhibitor of InhA enzyme. First we converted the selected acetophenones to appropriate alkynes. In second step, the synthesized alkynes and azide were reacted in Huisgen alkyne-azide cicloaddition catalysed by Cu(I) to give the final triazoles.
Unfortunately IC50 values of the synthesized compounds could not be determined, since the inhibition of InhA enzyme was too low. The only compound that exhibited minor activity at 100 µM was triazole 3. The modifications made to the lead compound have failed to produce effective inhibitors of InhA. Nevertheless, we have acquired new knowledge regarding structure-activity relationship of thiazole inhibitors of InhA. Additionally, all the synthesized compounds will be added to chemical library at the FFA and will be routinely tested on new targets, whereas prepared alkynes will be used as building blocks in the synthesis of other compounds.
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