Synthesis, in vitro antibacterial activity againstMycobacterium tuberculosis, and reverse docking-based target fishing of 1,4-benzoxazin-2-one derivatives

Seventeen 1,4-benzoxazin-2-ones bearing the enaminone moiety and three of their analogs were tested for the antibacterial activity againstMycobacterium tuberculosis(H37Rv). Minimal bactericidal concentrations (MBCs) were determined after 41 days of incubation by BACTEC. 1,4-Benzoxazin-2-ones bearing the unsubstituted benzo moiety showed the most promising activities (MBC = 5.00 mu g/ml). For most active compounds, antibacterial activities were determined daily during the 41 days. The most promising compound showed a bacteriostatic effect at a concentration of 0.31 mu g/ml on Day 4 of incubation, 0.62 mu g/ml on Day 6, 2.50 mu g/ml on Day 9, and 5.00 mu g/ml on Day 41. All studied compounds, along with some of their reported analogs, were docked to 35 proteins ofM. tuberculosisto find their potent targets in these organisms. As a result of reverse docking, aspartate 1-decarboxylase,panD, was selected as the most appropriate target. Docking of the most active compounds to mutantpanDfrom pyrazinamide-resistant strains ofM. tuberculosisimplies that they would not be active against these strains. Considering that most of pyrazinamide clinical resistance cases are due to loss-of-function mutations in pyrazinamidase,pncA, compounds from this study could be useful drugs for the treatment of some cases of pyrazinamide-resistant tuberculosis.

Automated summary

In this study, 17 1,4-benzoxazin-2-ones containing the enaminone moiety and their analogs were tested for antibacterial activity against Mycobacterium tuberculosis, with the unsubstituted benzo moiety showing the most promising activity. The most active compounds showed varying bacteriostatic effects over a 41-day incubation period. Docking of these compounds to mutant panD from pyrazinamide-resistant strains of M. tuberculosis indicated potential ineffectiveness against these strains. The study suggests that compounds from this research could be useful for treating some cases of pyrazinamide-resistant tuberculosis caused by loss-of-function mutations in pyrazinamidase, pncA.