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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 <jats:italic>N<\/jats:italic>\u2010acetyl moiety for a <jats:italic>N<\/jats:italic>\u2010carbamoyl group led to analogues with sub\u2010 and nanomolar potencies against <jats:italic>M. tuberculosis<\/jats:italic> H37Rv, as well as equipotent against drug\u2010susceptible and drug\u2010resistant <jats:italic>M. tuberculosis<\/jats:italic> isolates. The new <jats:italic>N<\/jats:italic>\u2010carbamoyl azaaurones exhibited improved microsomal stability, compared to their <jats:italic>N<\/jats:italic>\u2010acetylated 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<jats:sup>\u22128<\/jats:sup>, 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.<\/jats:p>","DOI":"10.1002\/cmdc.202300410","type":"journal-article","created":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T22:19:21Z","timestamp":1697494761000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Structural Optimization of Antimycobacterial Azaaurones Towards Improved Solubility and Metabolic Stability"],"prefix":"10.1002","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0560-4597","authenticated-orcid":false,"given":"Andr\u00e9","family":"Campani\u00e7o","sequence":"first","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o do Medicamento (iMed.ULisboa) Faculdade de Farm\u00e1cia Universidade de Lisboa  Av. 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