Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis, which most commonly affects the lungs. Tuberculosis is a major healthcare burden causing 1.3 million deaths every year. Mycobacterial cell wall is rich in lipids, and the major part of lipid com-ponents are fatty acids called mycolic acids. Enzymes within mycolic acid synthesis path-way are drug targets. One of those enzymes is InhA (enoyl acyl carrier protein), an enzyme which is targeted by isoniazid, a drug of first choice for tuberculosis treatment. Isoniazid is a prodrug and requires activation by KatG peroxidase. Since KatG is essential for activa-tion, mutation on KatG gene causes resistance of M. tuberculosis to isoniazid. Therefore research is conducted on direct InhA inhibitors, which do not require activation. One of direct InhA inhibitor classes discovered through high through-put screening are benzamide inhibitors, which show a good potential for further optimization.
In the master thesis our goal we synthesized seven benzamide inhibitors. Firstly, we syn-thesized compounds 4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-((2-(4-phenylthiazol-2-yl)cyclopentyl)benzamide and 4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-((2-(4-phenylthiazol-2-yl)cyclohexyl)benzamide. Since both compounds have a chiral center, we planed the synthesis to prepare both diastereomeres. Both diastereomeres of compound with cyclopentane ring and compound with cyclohexane ring exhibited very similar inhibi-tor potency in micro molar range. In the second part of the master thesis we focused on a synthesis of five different analogues of 4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl ben-zamide inhibitors. We used 2-phenilpiperidine, 2-phenilpirolidine, 2-phenilazetidine, 1-methyl-3-phenilpiperazine in 3-phenilmorpholine as substituents. Three of synthesized ana-logues exhibited inhibitor potency in low micro molar range. Compounds trans 4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-((2-(4-phenylthiazol-2-yl)cyclopentyl)benzamide and (4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)phenyl)(2-phenylpiperidin-1-yl)methanone also showed modest antibacterial activity. In this thesis, we researched structure-activity rela-tionship between different analogues of benzamide InhA inhibitors and their potency.