6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]thiazoles: Facile Synthesis and Comparative Appraisal Against Tuberculosis and Neglected Tropical Diseases

Bioorg Med Chem Lett. 2017 Jun 1;27(11):2583-2589. doi: 10.1016/j.bmcl.2017.03.069. Epub 2017 Mar 27.

Abstract

As part of a quest for backups to the antitubercular drug pretomanid (PA-824), we investigated the unexplored 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]-thiazoles and related -oxazoles. The nitroimidazothiazoles were prepared in high yield from 2-bromo-4-nitroimidazole via heating with substituted thiiranes and diisopropylethylamine. Equivalent examples of these two structural classes provided broadly comparable MICs, with 2-methyl substitution and extended aryloxymethyl side chains preferred; albeit, S-oxidised thiazoles were ineffective for tuberculosis. Favourable microsomal stability data for a biaryl thiazole (45) led to its assessment in an acute Mycobacterium tuberculosis mouse model, alongside the corresponding oxazole (48), but the latter proved to be more efficacious. In vitro screening against kinetoplastid diseases revealed that nitroimidazothiazoles were inactive versus leishmaniasis but showed interesting activity, superior to that of the nitroimidazooxazoles, against Chagas disease. Overall, "thio-delamanid" (49) is regarded as the best lead.

Keywords: Chagas disease; Delamanid; In vivo efficacy; Nitroimidazole; Tuberculosis.

MeSH terms

  • Animals
  • Antitubercular Agents / chemical synthesis*
  • Antitubercular Agents / pharmacology
  • Antitubercular Agents / therapeutic use
  • Chagas Disease / drug therapy
  • Disease Models, Animal
  • Mice
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects
  • Nitroimidazoles / chemistry*
  • Nitroimidazoles / pharmacology
  • Nitroimidazoles / therapeutic use
  • Oxazoles / chemistry
  • Oxazoles / pharmacology
  • Oxazoles / therapeutic use
  • Structure-Activity Relationship
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology
  • Thiazoles / therapeutic use
  • Tuberculosis / drug therapy

Substances

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