Structural Optimization of Antimycobacterial Azaaurones Towards Improved Solubility and Metabolic Stability

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.

New azaaurone derivatives as potential multitarget agents in HIV‐TB coinfection

“…The 1 H NMR analysis showed a mixture of isomers for the alkylated molecules (32-34) in a 1:0.1 (Z: E) ratio. [18] In the 1 H NMR spectra of intermediates 32-34, we observed the appearance of triplet signals corresponding to methylene hydrogens between 2.14 and 2.26 ppm. The terminal hydrogens of the triple bond appeared at approximately 4.…”

“…According to the values of chemical displacements in NMR analysis, the main product was the Z isomer, which is the most stable isomer. [18][19][20] The 1 H-NMR spectra for compounds 8-10 showed the absence of signals for the terminal hydrogens and the presence of a singlet relative to methylene hydrogens between 4.97 and 5.08 ppm, which indicates the absence of coupling.…”

“…These intermediates were reacted with acetic anhydride at 90°C, producing 16a,b, which subsequently underwent an intramolecular bimolecular nucleophilic substitution (S N 2) reaction using sodium hydride to form 17a,b. In parallel, the aldehydes used in the cross-aldolic condensation stage were obtained commercially or synthesized through the Suzuki reaction between p-bromobenzaldehyde (18) and the respective boronic acids (19)(20)(21)(22). [4,8] These new intermediates (23)(24)(25)(26)(27) can be hydrolyzed and subsequently alkylated or reacted directly with AZT via click chemistry reaction, according to the final product of interest (Scheme 1).…”

“…The hydrolysis products (28-31) were generated as Z isomers, described as thermodynamically more stable. [4,8,18] Based on the results obtained from NMR spectra, all acetylated intermediates had their configuration assigned to the Z isomer for the one with the highest abundance.…”

“…These values are consistent with those previously reported for (Z)-azaaurones. [4,8,[18][19][20][21] Finally, in the case of products 12-13, a singlet relative to the acetyl group at 2.09 ppm was observed.…”