Synthesis and antimycobacterial activity of imidazo[1,2-b][1,2,4,5]tetrazines

Eur J Med Chem. 2019 Sep 15;178:39-47. doi: 10.1016/j.ejmech.2019.05.081. Epub 2019 May 31.

Abstract

Tuberculosis (TB) has recently become the leading killer among infectious diseases. Multidrug and extensively drug-resistant Mycobacterium tuberculosis strains urge the need to develop anti-TB drugs with a novel mechanism of action. We describe synthesis of 22 novel imidazo[1,2-b][1,2,4,5]tetrazine derivatives with different substituents at C(3) and C(6) positions, and their antimycobacterial activity in vitro. 8 compounds show activity as potential serine/threonine protein kinase (STPK) inhibitors in M. smegmatis aphVIII+ test-system, which is characteristic for this class. 3 compounds out of 5 most active STPK inhibitors have a prominent minimal inhibitory concentration on M. tuberculosis H37Rv of 1 μg/ml. We were able to obtain M. smegmatis mc2 155 mutants resistant to 4 compounds and show that they do not have cross resistance with other drugs, but have a common mechanism of resistance among these 4 imidazo[1,2-b][1,2,4,5]tetrazines. Compound 3h seems the most promising, combining a predicted STPK inhibitor activity, the lowest MIC on M. tuberculosis and a low frequency of drug resistant mutants' emergence.

Keywords: CH-functionalization; Drug discovery; Drug resistance; Mycobacterium smegmatis; Mycobacterium tuberculosis; Tuberculosis; imidazo[1,2-b][1,2,4,5]tetrazine.

MeSH terms

  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Drug Resistance, Microbial / drug effects
  • Erythromycin / pharmacology
  • Heterocyclic Compounds, 2-Ring / chemical synthesis
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Imipenem / pharmacology
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Mycobacterium smegmatis / drug effects
  • Mycobacterium smegmatis / enzymology
  • Mycobacterium tuberculosis / drug effects
  • Ofloxacin / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Rifampin / pharmacology

Substances

  • Antitubercular Agents
  • Heterocyclic Compounds, 2-Ring
  • Imidazoles
  • Erythromycin
  • Imipenem
  • Ofloxacin
  • Protein-Serine-Threonine Kinases
  • Rifampin