Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines

J Antimicrob Chemother. 2005 Nov;56(5):968-74. doi: 10.1093/jac/dki319. Epub 2005 Sep 19.


Objectives: The aim of this study was to identify a candidate drug for clinical development from a previously synthesized combinatorial library based on the 1,2-ethylenediamine structure of ethambutol.

Methods: Sixty-nine of the most potent hits against Mycobacterium tuberculosis from the original studies were subjected to a sequential set of tests in vitro and in vivo--determination of MIC for M. tuberculosis H37Rv, cytotoxicity, intracellular antimycobacterial activity, permeability evaluation and in vivo efficacy testing.

Results: Twenty-seven compounds with MICs of < or = 15.6 microM were tested on Vero cells to determine in vitro cytotoxicity (IC50) and to establish a selectivity index (SI) (SI = IC50/MIC). Ten compounds with acceptable SI were tested for activity against intracellular bacteria--all were equivalent (within 1%) or superior to ethambutol and several demonstrated cidal activity. Five of the most potent compounds were tested for in vivo efficacy in a murine model of chronic tuberculosis infection.

Conclusion: Compound SQ109 with an MIC of 0.7-1.56 microM (H37Rv, Erdman and drug-resistant strains of M. tuberculosis), an SI of 16.7 and 99% inhibition activity against intracellular bacteria, demonstrated potency in vivo and limited toxicity in vitro and in vivo, and was selected for further development.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / isolation & purification*
  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / toxicity
  • Cell Survival / drug effects
  • Chlorocebus aethiops
  • Colony Count, Microbial
  • Combinatorial Chemistry Techniques*
  • Disease Models, Animal
  • Ethambutol / chemistry
  • Ethylenediamines / chemistry*
  • Mice
  • Mice, Inbred C57BL
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*
  • Tuberculosis / drug therapy*
  • Vero Cells


  • Antitubercular Agents
  • Ethylenediamines
  • ethylenediamine
  • Ethambutol