Design and Synthesis of 1-((1,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and N-Adamantan-2-yl-N'-((E)-3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine (SQ109) Pyrrole Hybrid Derivatives: Discovery of Potent Antitubercular Agents Effective against Multidrug-Resistant Mycobacteria

J Med Chem. 2016 Mar 24;59(6):2780-93. doi: 10.1021/acs.jmedchem.6b00031. Epub 2016 Mar 8.


Novel pyrroles have been designed, synthesized, and evaluated against mycobacterial strains. The pyrroles have originally been designed as hybrids of the antitubercular drugs BM212 (1) and SQ109 (2), which showed common chemical features with very similar topological distribution. A perfect superposition of the structures of 1 and 2 revealed by computational studies suggested the introduction of bulky substituents at the terminal portion of the pyrrole C3 side chain and the removal of the C5 aryl moiety. Five compounds showed high activity toward Mycobacterium tuberculosis, while 9b and 9c were highly active also against multidrug-resistant clinical isolates. Compound 9c showed low eukaryotic cell toxicity, turning out to be an excellent lead candidate for preclinical trials. In addition, four compounds showed potent inhibition (comparable to that of verapamil) toward the whole-cell drug efflux pump activity of mycobacteria, thus turning out to be promising multidrug-resistance-reversing agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / analogs & derivatives*
  • Adamantane / chemical synthesis
  • Adamantane / pharmacology
  • Antitubercular Agents / chemical synthesis*
  • Antitubercular Agents / pharmacology*
  • Carrier Proteins / drug effects
  • Cell Line
  • Cell Survival / drug effects
  • Computational Biology
  • Drug Design
  • Drug Resistance, Multiple, Bacterial / drug effects*
  • Ethylenediamines / chemical synthesis*
  • Ethylenediamines / pharmacology*
  • Humans
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Mycobacterium / drug effects
  • Mycobacterium tuberculosis / drug effects*
  • Pharmaceutical Preparations / metabolism
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacology*
  • Pyrroles / chemical synthesis*
  • Pyrroles / pharmacology*
  • Structure-Activity Relationship


  • Antitubercular Agents
  • Carrier Proteins
  • Ethylenediamines
  • N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine
  • Pharmaceutical Preparations
  • Piperazines
  • Pyrroles
  • Adamantane
  • BM 212