2. Academic Validation
  3. Hydride-induced Meisenheimer complex formation reflects activity of nitro aromatic anti-tuberculosis compounds

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

Affiliations

  • 1 Department of Chemistry and Biochemistry, University of Notre Dame Notre Dame IN 46556 USA mmiller1@nd.edu.
  • 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.

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