Tuberculosis is a chronic infectious disease which affects about nine million people each year around the world. It is caused by Mycobacterium Tuberculosis which is specific for its complex cell wall. One of its key building blocks are mycolic acids. InhA (2-trans-enoyl-ACP reductase) is an enzyme that is involved in the biosynthesis in the FASII system. The most commonly used medicament in the fight against tuberculosis is Isoniazid (INH), which acts as an InhA inhibitor. The key agent that makes Isoniazid effective is the KatG enzyme, which transforms it into an active form. Over the last decade, due to mutations in the katG gene Mycobacterium Tuberculosis resistance to INH has been increasing. New effective inhibitors are direct InhA inhibitors that block the target InhA without requiring bio-activation with the KatG enzyme. In the master thesis, we wanted to synthesize five derivatives, but we managed to completely synthesize only three of them and test them as inhibitors of the InhA. Our three synthesized compounds inhibit the activity of the InhA in the low micromolar range. Although the best inhibitors inhibit InhA is in the nanomolar range, these compounds provide a good starting point for further synthesis and optimization towards potentially new antituberculotics.
|
