Structural Optimization of Antimycobacterial Azaaurones Towards Improved Solubility and Metabolic Stability

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.

Automated summary

This study successfully improved the metabolic stability and solubility of N-acetyl azaaurones by replacing the N-acetyl moiety with a N-carbamoyl group. The new N-carbamoyl azaaurones exhibited potent antimycobacterial activity against drug-susceptible and drug-resistant M. tuberculosis isolates, with improved microsomal stability and kinetic solubility. These findings highlight the potential of azaaurones as antimycobacterial agents.