1. Academic Validation
  2. Discovery and optimization of benzotriazine di-N-oxides targeting replicating and nonreplicating Mycobacterium tuberculosis

Discovery and optimization of benzotriazine di-N-oxides targeting replicating and nonreplicating Mycobacterium tuberculosis

  • J Med Chem. 2012 Jul 12;55(13):6047-60. doi: 10.1021/jm300123s.
Sidharth Chopra 1 Gary A Koolpe Arlyn A Tambo-Ong Karen N Matsuyama Kenneth J Ryan Tran B Tran Rupa S Doppalapudi Edward S Riccio Lalitha V Iyer Carol E Green Baojie Wan Scott G Franzblau Peter B Madrid
Affiliations

Affiliation

  • 1 Center for Infectious Disease and Biodefense Research, Bioscience Division, SRI International, Menlo Park, CA 94025-3493, USA.
Abstract

Compounds bactericidal against both replicating and nonreplicating Mtb may shorten the length of TB treatment regimens by eliminating infections more rapidly. Screening of a panel of antimicrobial and Anticancer drug classes that are bioreduced into cytotoxic species revealed that 1,2,4-benzotriazine di-N-oxides (BTOs) are potently bactericidal against replicating and nonreplicating Mtb. Medicinal chemistry optimization, guided by semiempirical molecular orbital calculations, identified a new lead compound (20q) from this series with an MIC of 0.31 μg/mL against H37Rv and a cytotoxicity (CC(50)) against Vero cells of 25 μg/mL. 20q also had equivalent potency against a panel of single-drug resistant strains of Mtb and remarkably selective activity for Mtb over a panel of Other pathogenic Bacterial strains. 20q was also negative in a L5178Y MOLY assay, indicating low potential for genetic toxicity. These data along with measurements of the physiochemical properties and pharmacokinetic profile demonstrate that BTOs have the potential to be developed into a new class of antitubercular drugs.

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