Straightforward palladium-mediated synthesis and biological evaluation of benzo[j]phenanthridine-7,12-diones as anti-tuberculosis agents

• DOI: 10.1016/j.ejmech.2011.11.033
• Publication Date: 2011-12-07T12:24:21Z
• Authors: Davie Cappoen; Jan Jacobs; Tuyen Nguyen Van; Sven Claessens; Gaston Diels; Roel Anthonissen; Thorbjorg Einarsd...; Maryse Fauville; Luc Verschaeve; Kris Huygen; Norbert De Kimpe
• Keywords: Magnetic Resonance Spectroscopy; Molecular Structure; Cell Survival; Antitubercular Agents; Microbial Sensitivity Tests; Mycobacterium tuberculosis; 01 natural sciences; Mass Spectrometry; Cell Line; Phenanthridines; 3. Good health; 0104 chemical sciences; Inhibitory Concentration 50; Mice; Spectroscopy, Fourier Transform Infrared; Hepatocytes; Animals; Humans; Comet Assay; Palladium

In 1991, WHO recognized the resurgence of tuberculosis as a global health problem. Although modern chemotherapy is effective against the causative pathogen Mycobacterium tuberculosis, the current drug regimens have failed to eradicate the disease. The success of the pathogen, partially attributed to drug resistance, necessitates the development of novel anti-tuberculosis drugs. Benzo[j]phenanthridine-7,12-diones, tetracyclic derivatives of the natural product benz[g]isoquinoline-5,10-dione, were conveniently synthesized via palladium-catalyzed intramolecular cyclization of N-methanesulfonyl-3-bromo-2-(arylamino)methyl-1,4-naphthoquinones. Here we report on the bioactivity of eight benzo[j]phenanthridine-7,12-dione derivatives as candidate drug molecules against M. tuberculosis and on their cytotoxicity on C3A human hepatocytes. The strongest antimicrobial activity (as detected by growth inhibition of bacteria, using luminometry and BACTEC 460-TB) and lowest cytotoxicity was found for 3-methylbenzo[j]phenanthridine-7,12-dione 5e, which was also effective in targeting intracellular M. tuberculosis (in murine J774 macrophages) and was not genotoxic for C3A hepatocytes.