Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis. It is the second most common infectious disease in the world. More than 10 million people become infected each year, making it a major global health problem. Treatment of tuberculosis is complex and time-consuming, but the major challenge is resistance of some M. tuberculosis strains. The mycobacterial cell wall has a unique structure, the key components of which are mycolic acids. The enzymes involved in mycolic acid biosynthesis are the main targets of the antituberculotic drugs. Enzyme InhA (trans-2-enoyl-ACP (acyl carrier protein) reductase) is one of the targets. Isoniazid is an inhibitor of the InhA enzyme and it is the first-line treatment for latent and active tuberculosis. Isoniazid is a prodrug and therefore needs to be activated by the mycobacterial enzyme catalase-peroxidase KatG in order to work. Most isoniazid resistant strains have a mutation in the KatG gene that causes isoniazid to be ineffective. The development of antituberculotic drugs has therefore focused on the search for direct inhibitors of the InhA enzyme that do not require activation to function. The tetrahydropyran derivative 4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide, detected by high-throughput screening, proved to be a promising lead compound for new direct inhibitors of the InhA enzyme. As part of the master's thesis, we wanted to synthesise six analogues of the lead compound with minor structural modifications to explore the chemical space of the InhA binding site. We successfully synthesised three compounds which were tested against the isolated InhA enzyme and we determined the IC50 value of the compound. All three compounds showed inhibitory activity. However, all IC50s were found to be weaker than the lead compound. This confirmed the previously known observation that the InhA binding site is very sensitive to even small structural changes.
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