Pharmacokinetically-guided lead optimization of nitrofuranylamide anti-tuberculosis agents

AAPS J. 2008;10(1):157-65. doi: 10.1208/s12248-008-9017-8. Epub 2008 Mar 14.


In an effort to develop novel and more potent therapies to treat tuberculosis, a new class of chemical agents, nitrofuranylamides, is being developed. The present study examines biopharmaceutic properties and preclinical pharmacokinetics of nitrofuranylamides at early stages of drug discovery to accelerate the optimization of leads into development candidates. The first tested compound, Lee 562, had high anti-tuberculosis activity in vitro, but exhibited poor metabolic stability resulting in a high systemic clearance, a short elimination half-life and low oral bioavailability in vivo in rats. Thus, two follow-up compounds were designed and tested that included structural modifications for increased metabolic stability. Both compounds showed improved metabolic stability compared to Lee 562, with Lee 878 being much more stable than Lee 952. As a consequence, the oral bioavailability of Lee 878 reached approximately 27% compared to 16% for the other two compounds. This observation prompted us to select compounds based on metabolic stability screening and a new set of nine compounds with high in vitro activity were tested for metabolic stability. The most stable compound in the assay, Lee 1106 was selected for further pharmacokinetic evaluation in rats. Surprisingly, Lee 1106 exhibited poor oral bioavailability, 4.6%. Biopharmaceutic evaluation of the compound showed that the compound has poor aqueous solubility and a high clogP. Based on these results, a screening paradigm was developed for optimization of the nitrofuranylamide lead compounds in a timely and cost-effective manner that might also be applicable to other classes of anti-infective drugs.

Publication types

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

MeSH terms

  • Animals
  • Antitubercular Agents / blood
  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacokinetics*
  • Male
  • Nitrofurans / blood
  • Nitrofurans / chemistry*
  • Nitrofurans / pharmacokinetics*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship


  • Antitubercular Agents
  • Nitrofurans