Antitubercular nitrofuran isoxazolines with improved pharmacokinetic properties.

Abstract

A series of tetracyclic nitrofuran isoxazoline anti-tuberculosis agents was designed and synthesized to improve the pharmacokinetic properties of an initial lead compound, which had potent anti-tuberculosis activity but suffered from poor solubility, high protein binding and rapid metabolism. In this study, structural modifications were carried on the outer phenyl and piperidine rings to introduce solubilizing and metabolically blocking functional groups. The compounds generated were evaluated for their in vitro antitubercular activity, bacterial spectrum of activity, solubility, permeability, microsomal stability and protein binding. Pharmacokinetic profiles for the most promising candidates were then determined. Compounds with phenyl morpholine and pyridyl morpholine outer rings were found to be the most potent anti-tuberculosis agents in the series. These compounds retained a narrow antibacterial spectrum of activity, with weak anti-Gram positive and no Gram negative activity, as well as good activity against non-replicating Mycobacterium tuberculosis in a low oxygen model. Overall, the addition of solubilizing and metabolically blocked outer rings did improve solubility and decrease protein binding as designed. However, the metabolic stability for compounds in this series was generally lower than desired. The best three compounds selected for in vivo pharmacokinetic testing all showed high oral bioavailability, with one notable compound showing a significantly longer half-life and good tolerability supporting its further advancement.

• Authors: Rakesh, David Bruhn, Dora B Madhura, Marcus Maddox, Robin B Lee, Ashit Trivedi, Lei Yang, Michael S Scherman, Janet C Gilliland, Veronica Gruppo, Michael R McNeil, Anne J Lenaerts, Bernd Meibohm, Richard E Lee
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 20 Pg. 6063-72 (Oct 15 2012) ISSN: 1464-3391 [Electronic] England
• PMID: 22995771 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Antitubercular Agents
• Isoxazoles
• Nitrofurans

Topics

• Animals
• Antitubercular Agents (chemical synthesis, chemistry, pharmacokinetics)
• Caco-2 Cells
• Cell Survival (drug effects)
• Half-Life
• Humans
• Isoxazoles (chemistry)
• Mice
• Microbial Sensitivity Tests
• Microsomes (metabolism)
• Mycobacterium tuberculosis (drug effects)
• Nitrofurans (chemical synthesis, chemistry, pharmacokinetics)
• Rats
• Solubility
• Structure-Activity Relationship