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.

Infections Caused by Mycobacterium tuberculosis in Recipients of Hematopoietic Stem Cell Transplantation

“…Resistance to anti-TB chemotherapy can be attributed to: (1) failure to complete the course of anti-TB treatment, (2) weak health-care infrastructures particularly in third world countries, (3) lack of diagnostic techniques and drug susceptibility testing (DST), and (4) having no new anti-TB drugs available since the 1960s till the turn of the century (1, 9). In a survey performed by the WHO in the year 1997, drug resistant TB was found in all 35 countries included in that survey and in the last survey done in the year 2000, drug resistant TB was documented in all 100 countries surveyed (1, 10). …”

Synthesis, biological evaluation and 3D QSAR study of 2,4-disubstituted quinolines as anti-tuberculosis agents

“…A freshly prepared solution of ammonium persulfate (3 mmol) in water (5 mL (11)(12)(13)(14)(15)(16)(17)(18)(19) M A N U S C R I P T …”

“…More recently, a large number of reports on the design of synthesis of several new and versatile classes of anti-tuberculosis agents have appeared [10][11][12][13][14].…”

Synthesis and in vitro investigation of halogenated 1,3‐bis(4‐nitrophenyl)triazenide salts as antitubercular compounds

“…[14,15] After 7 days of exposure, the IC 50 and IC 90 were evaluated by testing serial dilutions of the investigated 1,3-diaryltriazenides 1-8. As reported previously in the literature, this luminometric technique offers a rapid, cheap and reproducible tool to test the efficacy of potential novel antitubercular compounds, replacing the fastidious CFU enumeration on agar.…”