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

Arch Pharm (Weinheim). 2021 Feb;354(2):e2000199. doi: 10.1002/ardp.202000199. Epub 2020 Oct 14.


Seventeen 1,4-benzoxazin-2-ones bearing the enaminone moiety and three of their analogs were tested for the antibacterial activity against Mycobacterium 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 µg/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 µg/ml on Day 4 of incubation, 0.62 µg/ml on Day 6, 2.50 µg/ml on Day 9, and 5.00 µg/ml on Day 41. All studied compounds, along with some of their reported analogs, were docked to 35 proteins of M. tuberculosis to 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 mutant panD from pyrazinamide-resistant strains of M. tuberculosis implies 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.

Keywords: 1,4‐benzoxazin‐2‐one; Mycobacterium tuberculosis; antibacterial activity; molecular docking; panD.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Benzoxazines / chemical synthesis
  • Benzoxazines / chemistry
  • Benzoxazines / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation*
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*


  • Anti-Bacterial Agents
  • Benzoxazines