Azaaurones as Potent Antimycobacterial Agents Active against MDR‐ and XDR‐TB | Zendy

Campaniço André | Zendy; Carrasco Marta P. | Zendy; Njoroge Mathew | Zendy; Seldon Ronnett | Zendy; Chibale Kelly | Zendy; Perdigão João | Zendy; Portugal Isabel | Zendy; Warner Digby F. | Zendy; Moreira Rui | Zendy; Lopes Francisca | Zendy

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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.

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