Synthesis and Structure-Activity Studies of Biphenyl Analogues of the Tuberculosis Drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)

J Med Chem. 2010 Jan 14;53(1):282-94. doi: 10.1021/jm901207n.

Abstract

A series of biphenyl analogues of the new tuberculosis drug PA-824 was prepared, primarily by coupling the known (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol with iodobenzyl halides, followed by Suzuki coupling of these iodides with appropriate arylboronic acids or by assembly of the complete biaryl side chain prior to coupling with the above alcohol. Antitubercular activity was determined under both replicating (MABA) and nonreplicating (LORA) conditions. para-Linked biaryls were the most active, followed by meta-linked and then ortho-linked analogues. A more detailed study of a larger group of para-linked analogues showed a significant correlation between potency (MABA) and both lipophilicity (CLOGP) and the electron-withdrawing properties of terminal ring substituents ( summation operatorsigma). Selected compounds were evaluated for their efficacy in a mouse model of acute Mycobacterium tuberculosis infection. In vivo activity correlated well with the stability of compounds to microsomal metabolism. Three compounds bearing combinations of lipophilic, electron-withdrawing groups achieved >200-fold higher efficacies than the parent drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / chemical synthesis*
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Mice
  • Mice, Inbred BALB C
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*
  • Nitroimidazoles / chemical synthesis*
  • Nitroimidazoles / chemistry
  • Nitroimidazoles / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Antitubercular Agents
  • Nitroimidazoles
  • pretomanid