Premium
Azaaurones as Potent Antimycobacterial Agents Active against MDR‐ and XDR‐TB
Author(s) -
Campaniço André,
Carrasco Marta P.,
Njoroge Mathew,
Seldon Ronnett,
Chibale Kelly,
Perdigão João,
Portugal Isabel,
Warner Digby F.,
Moreira Rui,
Lopes Francisca
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900289
Subject(s) - antimycobacterial , mycobacterium tuberculosis , tuberculosis , chemistry , metabolite , stereochemistry , pharmacology , multiple drug resistance , biology , drug resistance , microbiology and biotechnology , medicine , biochemistry , pathology
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 μ m , whereas azaaurones and N ‐acetylazaaurones emerged as the most potent compounds, with nine derivatives displaying MIC 99 values ranging from 0.4 to 2.0 μ m . 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.