Synthesis and structure-activity relationships for extended side chain analogues of the antitubercular 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. 2015 Apr 9;58(7):3036-59. doi: 10.1021/jm501608q. Epub 2015 Mar 27.


Novel extended side chain nitroimidazooxazine analogues featuring diverse linker groups between two aryl rings were studied as a potential strategy to improve solubility and oral activity against chronic infection by Mycobacterium tuberculosis. Both lipophilic and highly polar functionalities (e.g., carboxamide, alkylamine, piperazine, piperidine, but not sulfonamide) were well tolerated in vitro, and the hydrophilic linkers provided some solubility improvements, particularly in combination with pyridine rings. Most of the 18 compounds further assessed showed high microsomal stabilities, although in the acute infection mouse model, just one stilbene (6-fold) and two pyridine-containing acetylene derivatives (5-fold and >933-fold) gave in vivo efficacies notably superior to the clinical stage compound pretomanid (PA-824). The most efficacious analogue also displayed outstanding in vivo activity in the stringent chronic model (up to 24-fold better than the drug delamanid and 4-fold greater than our previous best phenylpyridine candidate), with favorable pharmacokinetics, including good oral bioavailability in the rat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antitubercular Agents / chemical synthesis*
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacokinetics
  • Antitubercular Agents / pharmacology*
  • Biological Availability
  • Chemistry Techniques, Synthetic
  • Chronic Disease
  • Disease Models, Animal
  • Humans
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred Strains
  • Microbial Sensitivity Tests
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Mycobacterium tuberculosis / drug effects
  • Nitroimidazoles / chemistry*
  • Nitroimidazoles / pharmacology
  • Oxazoles / pharmacology
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Tuberculosis / drug therapy
  • Tuberculosis / microbiology


  • Antitubercular Agents
  • Nitroimidazoles
  • OPC-67683
  • Oxazoles
  • pretomanid