Hydride-induced Meisenheimer complex formation reflects activity of nitro aromatic anti-tuberculosis compounds

  • RSC Med Chem. 2021 Jan 4;12(1):62-72. doi: 10.1039/d0md00390e.
Rui Liu  1 ,  Lowell Markley  1 ,  Patricia A Miller  1 ,  Scott Franzblau  2 ,  Gauri Shetye  2 ,  Rui Ma  2 ,  Karin Savková  3 ,  Katarína Mikušová  3 ,  Bei Shi Lee  4 ,  Kevin Pethe  4  5 ,  Garrett C Moraski  6 ,  Marvin J Miller  1
Affiliations
  • 1. Department of Chemistry and Biochemistry, University of Notre Dame Notre Dame IN 46556 USA [email protected].
  • 2. Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago 833 South Wood Street Chicago Il 60612 USA.
  • 3. Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava Ilkovičova 6 84215 Bratislava Slovakia.
  • 4. School of Biological Sciences, Nanyang Technological University Singapore 637551.
  • 5. Lee Kong Chian School of Medicine, Nanyang Technological University Singapore 636921.
  • 6. Department of Chemistry and Biochemistry, Montana State University Bozeman MT 59717 USA.
PMID: 34046598 DOI: 10.1039/d0md00390e
Abstract

The formation efficiency of hydride-induced Meisenheimer complexes of nitroaromatic compounds is consistent with their anti-TB activities exemplied by MDL860 and benzothiazol N-oxide (BTO) analogs. Herein we report that nitro cyano phenoxybenzenes (MDL860 and analogs) reacted slowly and incompletely which reflected their moderate anti-TB activity, in contrast to the instantaneous reaction of BTO derivatives to quantitatively generate Meisenheimer complexes which corresponded to their enhanced anti-TB activity. These results were corroborated by mycobacterial and radiolabelling studies that confirmed inhibition of the DprE1 enzyme by BTO derivatives but not MDL860 analogs.