| Despite the widespread use of chemotherapeutic agents, an estimated one-third of the global population is infected with Mycobacterium tuberculosis and two million lives are consumed annually by this pandemic disease. In order to discover and develop new anti-tuberculosis drugs, two classes of compounds---carbazole and 1,2,3,4-tetrahydro-beta-carboline---were synthesized and evaluated. Structure-activity relationships study of the 1,2,3,4-tetrahydro-beta-carboline series revealed that substitutions at C-1 and N-2 are crucial for anti-tuberculosis activity. Discovery of two compounds with submicromolar activity and non-toxicity against the two mammalian lines tested invited further study, including spectrums of activity, minimum bactericidal concentration, metabolic stability, pharmacokinetics and in vivo efficacy. Studied revealed that the 1,2,3,4-tetrahydro-beta-carboline series is selective towards the Mycobacterium tuberculosis complex. Different oral formulations of ITR406 indicated that PEG400 formulation provided the compound in solution, thereby resulting in greater oral bioavailability. Based on the findings, 1,2,3,4-tetrahydro-beta-carboline may be potential anti-tuberculosis lead candidates. |
