Azaaurones as Potent Antimycobacterial Agents Active against MDR- and XDR-TB.

Abstract

Herein we report the screening of a small library of aurones and their isosteric counterparts, azaaurones and N-acetylazaaurones, against Mycobacterium tuberculosis. Aurones were found to be inactive at 20 μm, whereas azaaurones and N-acetylazaaurones emerged as the most potent compounds, with nine derivatives displaying MIC99 values ranging from 0.4 to 2.0 μm. In addition, several N-acetylazaaurones were found to be active against multidrug-resistant (MDR) and extensively drug-resistant (XDR) clinical M. tuberculosis isolates. The antimycobacterial mechanism of action of these compounds remains to be determined; however, a preliminary mechanistic study confirmed that they do not inhibit the mycobacterial cytochrome bc1 complex. Additionally, microsomal metabolic stability and metabolite identification studies revealed that N-acetylazaaurones are deacetylated to their azaaurone counterparts. Overall, these results demonstrate that azaaurones and their N-acetyl counterparts represent a new entry in the toolbox of chemotypes capable of inhibiting M. tuberculosis growth.

• Authors: André Campaniço, Marta P Carrasco, Mathew Njoroge, Ronnett Seldon, Kelly Chibale, João Perdigão, Isabel Portugal, Digby F Warner, Rui Moreira, Francisca Lopes
• Journal: ChemMedChem (ChemMedChem) Vol. 14 Issue 16 Pg. 1537-1546 (08 20 2019) ISSN: 1860-7187 [Electronic] Germany
• PMID: 31294529 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antitubercular Agents
• Benzofurans
• Indoles
• Small Molecule Libraries

Topics

• Animals
• Antitubercular Agents (chemical synthesis, metabolism, pharmacology)
• Benzofurans (chemical synthesis, metabolism, pharmacology)
• Drug Resistance, Multiple, Bacterial (drug effects)
• Drug Stability
• HEK293 Cells
• Humans
• Indoles (chemical synthesis, metabolism, pharmacology)
• Mice
• Microbial Sensitivity Tests
• Microsomes, Liver (metabolism)
• Mycobacterium tuberculosis (drug effects)
• Small Molecule Libraries (chemical synthesis, metabolism, pharmacology)