Publication: Azaaurones as potent antimycobacterial agents active against MDR- and XDR-TB
Campanico, A Carrasco, M.P Njoroge, M Seldon, R Chibale, K Perdigao, J Portugal, I Warner, D.F Moreira, R Lopes, F
Campanico, A
Carrasco, M.P
Njoroge, M
Seldon, R
Chibale, K
Perdigao, J
Portugal, I
Warner, D.F
Moreira, R
Lopes, F
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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.
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Date
2019
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Wiley Online Library
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Keywords
Mycobacterium tuberculosis,Multidrug-resistant tuberculosis,Azaaurones,Drug discovery
Citation
Campaniço A, Carrasco MP, Njoroge M, Seldon R, et al. Azaaurones as potent antimycobacterial agents active against MDR- and XDR-TB. ChemMedChem. 2019 Aug 20;14(16):1537-1546. doi: 10.1002/cmdc.201900289.