Synthesis, anti-mycobacterial activity and DNA sequence-selectivity of a library of biaryl-motifs containing polyamides

Bioorg Med Chem. 2015 Jul 1;23(13):3705-11. doi: 10.1016/j.bmc.2015.04.001. Epub 2015 Apr 8.

Abstract

The alarming rise of extensively drug-resistant tuberculosis (XDR-TB) strains, compel the development of new molecules with novel modes of action to control this world health emergency. Distamycin analogues containing N-terminal biaryl-motifs 2(1-5)(1-7) were synthesised using a solution-phase approach and evaluated for their anti-mycobacterial activity and DNA-sequence selectivity. Thiophene dimer motif-containing polyamide 2(2,6) exhibited 10-fold higher inhibitory activity against Mycobacterium tuberculosis compared to distamycin and library member 2(5,7) showed high binding affinity for the 5'-ACATAT-3' sequence.

Keywords: Anti-tubercular agents; Antibiotic resistance; Combinatorial chemistry; DNA-minor groove ligands; Distamycin; Whole cell phenotypic evaluation.

MeSH terms

  • Antitubercular Agents / chemical synthesis*
  • Antitubercular Agents / pharmacology
  • Binding Sites
  • Combinatorial Chemistry Techniques
  • DNA Footprinting
  • DNA, Bacterial / antagonists & inhibitors*
  • DNA, Bacterial / chemistry
  • Distamycins / chemical synthesis*
  • Distamycins / pharmacology
  • Ligands
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Mycobacterium tuberculosis / chemistry
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / growth & development
  • Nylons / chemical synthesis*
  • Nylons / pharmacology
  • Small Molecule Libraries / chemical synthesis*
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship
  • Thiophenes / chemistry

Substances

  • Antitubercular Agents
  • DNA, Bacterial
  • Distamycins
  • Ligands
  • Nylons
  • Small Molecule Libraries
  • Thiophenes