1,2,3,4,8,9,10,11-Octahydrobenzo[j]phenanthridine-7,12-diones as New Leads against Mycobacterium tuberculosis

• Published in: Journal of medicinal chemistry Vol. 57; no. 7; pp. 2895 - 2907
• Main Authors: Cappoen, Davie, Claes, Pieter, Jacobs, Jan, Anthonissen, Roel, Mathys, Vanessa, Verschaeve, Luc, Huygen, Kris, Kimpe, Norbert De
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.04.2014; Amer Chemical Soc
• Subjects: Animals; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Cell Proliferation - drug effects; Chemistry, Medicinal; Comet Assay; DNA Damage; Drug Design; Drug Resistance, Multiple - drug effects; Life Sciences & Biomedicine; Macrophages - cytology; Macrophages - drug effects; Mice; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - growth & development; Pharmacology & Pharmacy; Phenanthridines - chemistry; Phenanthridines - pharmacology; Science & Technology; Structure-Activity Relationship; Tuberculosis - drug therapy; PATHOGENESIS; ASSAY; ANALOGS; ANGUCYCLINONE; MACROPHAGES; INFECTION; DERIVATIVES
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm401735w

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.