title: 1,2,3,4,8,9,10,11-octahydrobenzo[j]phenanthridine-7,12-diones as new leads against Mycobacterium tuberculosis.
abstract: Tuberculosis (TB) continues to be a worldwide health problem with over 1.4 million deaths each year. Despite efforts to develop more effective vaccines, more reliable diagnostics, and chemotherapeutics, tuberculosis remains a threat to global health, fueled by the HIV pandemic and the rapid generation of drug resistance. The exploration of novel drugs to serve as a companion drug for existing drugs is of paramount importance. As part of our program to design new 2-aza-anthraquinones with antimycobacterial activity, various tetrahydro- and octahydrobenzo[j]phenanthridinediones were synthesized. These compounds showed high in vitro potency against Mycobacterium tuberculosis, the etiological agent of TB and against other clinically relevant mycobacterial species at submicromolar concentrations. The susceptibility of a multidrug resistant strain toward these compounds and their ability to target intracellular replicating Mycobacterium tuberculosis was demonstrated. Next to the acute toxicity, the genotoxicity of these compounds was investigated. Often overlooked in studies, genotoxicity could be dismissed for the investigated compounds, making them a promising scaffold in TB drug research.
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: Pieter
authors.initials: P
authors.lastname: Claes
authors.forename: Jan
authors.initials: J
authors.lastname: Jacobs
authors.forename: Roel
authors.initials: R
authors.lastname: Anthonissen
authors.forename: Vanessa
authors.initials: V
authors.lastname: Mathys
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 / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D020552:Comet Assay; D004249:DNA Damage; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D010617:Phenanthridines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D010617:Phenanthridines