Campanico, ACarrasco, M.PNjoroge, MSeldon, RChibale, KPerdigao, JPortugal, IWarner, D.FMoreira, RLopes, F2024-06-092024-06-092019Campaniço 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.https://doi.org/10.1002/cmdc.201900289https://pubmed.ncbi.nlm.nih.gov/31294529/https://hdl.handle.net/11288/596536Herein 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.enMycobacterium tuberculosisMultidrug-resistant tuberculosisAzaauronesDrug discoveryArticleChemMedChem