@article{Campanico2023,
abstract = {While N‐acetyl azaaurones have already been disclosed for their potential against tuberculosis (TB), their low metabolic stability remains an unaddressed liability. We now report a study designed to improve the metabolic stability and solubility of the azaaurone scaffold and to identify the structural requirements for antimycobacterial activity. Replacing the N‐acetyl moiety for a N‐carbamoyl group led to analogues with sub‐ and nanomolar potencies against M. tuberculosis H37Rv, as well as equipotent against drug‐susceptible and drug‐resistant M. tuberculosis isolates. The new N‐carbamoyl azaaurones exhibited improved microsomal stability, compared to their N‐acetylated counterparts, with several compounds displaying moderate to high kinetic solubility. The frequency of spontaneous resistance to azaaurones was observed to be in the range of 10‐8, a value that is comparable to current TB drugs in the market. Overall, these results reveal that azaaurones are amenable to structural modifications to improve metabolic and solubility liabilities, and highlight their potential as antimycobacterial agents.},
author = {Campani{\c{c}}o, Andr{\'{e}} and Harjivan, Shrika G and Freitas, Elisabete and Serafini, Marco and Gaspar, Manuela M and Capela, Rita and Gomes, Pedro and Jordaan, Audrey and Madureira, Ana M and Andr{\'{e}}, V{\^{a}}nia and Silva, Andreia B and {Teresa Duarte}, M and Portugal, Isabel and Perdig{\~{a}}o, Jo{\~{a}}o and Moreira, Rui and Warner, Digby F and Lopes, Francisca},
doi = {10.1002/CMDC.202300410},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Campani{\c{c}}o et al. - 2023 - Structural optimization of antimycobacterial azaaurones towards improved solubility and metabolic stability.pdf:pdf},
issn = {1860-7187},
journal = {ChemMedChem},
keywords = {OA,activity relationships,azaaurones * M. tuberculosis * drug discovery * dr,fund{\_}not{\_}ack,original,resistant tuberculosis * Structure},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {oct},
pages = {e202300410},
pmid = {37845182},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Structural optimization of antimycobacterial azaaurones towards improved solubility and metabolic stability}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1002/cmdc.202300410 https://onlinelibrary.wiley.com/doi/abs/10.1002/cmdc.202300410 https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202300410},
year = {2023}
}

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Replacing the N‐acetyl moiety for a N‐carbamoyl group led to analogues with sub‐ and nanomolar potencies against M. tuberculosis H37Rv, as well as equipotent against drug‐susceptible and drug‐resistant M. tuberculosis isolates. The new N‐carbamoyl azaaurones exhibited improved microsomal stability, compared to their N‐acetylated counterparts, with several compounds displaying moderate to high kinetic solubility. The frequency of spontaneous resistance to azaaurones was observed to be in the range of 10‐8, a value that is comparable to current TB drugs in the market. 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