Structural Optimization of Antimycobacterial Azaaurones Towards Improved Solubility and Metabolic Stability

• DOI: 10.1002/cmdc.202300410
• Publication Date: 2023-10-17T02:19:21Z
• Authors: André Campaniço; Shrika G. Harjivan; Elisabete Freitas; Marco Serafini; M. Manuela Gaspar; Rita Capela; Pedro Gomes; Audrey Jordaan; Ana M. Madureira; Vânia André; Andreia B. Silva; M. Teresa Duarte; Isabel Portugal; João Perdigão; Rui Moreira; Digby F. Warner; Francisca Lopes
• Keywords: Antimycobacterial; Metabolic stability; Moiety

While N-acetyl azaaurones have already been disclosed for their potential against tuberculosis (TB), low metabolic stability remains an unaddressed liability. We now report a study designed to improve the and solubility of azaaurone scaffold identify structural requirements antimycobacterial activity. Replacing moiety N-carbamoyl group led analogues with sub- nanomolar potencies M. H37Rv, as well equipotent drug-susceptible drug-resistant isolates. The new exhibited improved microsomal stability, compared N-acetylated counterparts, several compounds displaying moderate high kinetic solubility. frequency spontaneous resistance was observed be in range 10