title: Straightforward palladium-mediated synthesis and biological evaluation of benzo[j]phenanthridine-7,12-diones as anti-tuberculosis agents.
abstract: 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.
authors.affiliation: Service Immunology, O.D. Communicable & Infectious Diseases, Scientific Institute of Public Health (Site Ukkel), Engelandstraat 642, B-1180 Ukkel, Belgium.
authors.forename: Davie
authors.initials: D
authors.lastname: Cappoen
authors.forename: Jan
authors.initials: J
authors.lastname: Jacobs
authors.forename: Tuyen
authors.initials: T
authors.lastname: Nguyen Van
authors.forename: Sven
authors.initials: S
authors.lastname: Claessens
authors.forename: Gaston
authors.initials: G
authors.lastname: Diels
authors.forename: Roel
authors.initials: R
authors.lastname: Anthonissen
authors.forename: Thorbjorg
authors.initials: T
authors.lastname: Einarsdottir
authors.forename: Maryse
authors.initials: M
authors.lastname: Fauville
authors.forename: Luc
authors.initials: L
authors.lastname: Verschaeve
authors.forename: Kris
authors.initials: K
authors.lastname: Huygen
authors.forename: Norbert
authors.initials: N
authors.lastname: De Kimpe
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D010165:Palladium / Q000737:chemistry*; D010617:Phenanthridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000995:Antitubercular Agents; D010617:Phenanthridines; D010165:Palladium