Abstract

Tuberculosis is the leading AIDS associated opportunistic infection found in non-industrialized nations of the world. There is an urgent need to develop new, potent, fast acting anti-tuberculosis drugs that can be used in conjunction with drugs used to treat HIV infections. Towards these ends we propose to explore and develop a novel class of nitrofuranyl amides as new anti-tuberculosis agents. This series of compounds is particularly attractive for TB drug development because of its ease of synthesis allowing for rapid synthesis of analogs in this proposal and could ultimately lead to an inexpensive drug. The goals of this proposal are to enhance the activity of the series in vitro and in vivo and to produce viable preclinical drug candidates. Computational drug design methods and modern medicinal chemistry synthesis techniques will be used to design and synthesize further compound generations. A complete microbiological and biochemical assessment of the nitrofuranyl series will be performed. MIC and MBC determinations for the new generations of compounds will be determined against various M. tuberculosis strains including H37Rv and multidrug resistant tuberculosis. The resistance frequency of M. tuberculosis to the lead compounds will be examined and cross resistance to other anti-tuberculosis drugs will be investigated. Synergy tests will be performed with other anti-tuberculosis drugs and the cytotoxicity of the compounds determined. The mechanism of action of these inhibitors will be studied. The effectiveness of the leads against latent tuberculosis will be evaluated using an in vitro assay of M. tuberculosis grown under low oxygen conditions. Maximum tolerated dose assays and basic bioavailability assays will be performed on the lead compounds. Compounds with good pharmacological profiles will then be tested using a rapid in vivo model. The in vivo activity is then confirmed using the standard TB mouse model. The basic pharmacokinetic and biopharmaceutic properties of leads will be characterized in vivo.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI062415-02
Application #
6895786
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Goldman, Robert C
Project Start
2004-05-20
Project End
2008-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$419,298
Indirect Cost

  Institution

Name
University of Tennessee Health Science Center
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163

  Publications

Rakesh; Bruhn, David F; Scherman, Michael S et al. (2016) Synthesis and evaluation of pretomanid (PA-824) oxazolidinone hybrids. Bioorg Med Chem Lett 26:388-391
North, E Jeffrey; Jackson, Mary; Lee, Richard E (2014) New approaches to target the mycolic acid biosynthesis pathway for the development of tuberculosis therapeutics. Curr Pharm Des 20:4357-78
Rakesh; Bruhn, David F; Scherman, Michael S et al. (2014) Pentacyclic nitrofurans with in vivo efficacy and activity against nonreplicating Mycobacterium tuberculosis. PLoS One 9:e87909
Trivedi, Ashit; Lee, Richard E; Meibohm, Bernd (2013) Applications of pharmacometrics in the clinical development and pharmacotherapy of anti-infectives. Expert Rev Clin Pharmacol 6:159-70
North, E Jeffrey; Scherman, Michael S; Bruhn, David F et al. (2013) Design, synthesis and anti-tuberculosis activity of 1-adamantyl-3-heteroaryl ureas with improved in vitro pharmacokinetic properties. Bioorg Med Chem 21:2587-99
Rakesh; Bruhn, David; Madhura, Dora B et al. (2012) Antitubercular nitrofuran isoxazolines with improved pharmacokinetic properties. Bioorg Med Chem 20:6063-72
Hurdle, Julian G; O'Neill, Alex J; Chopra, Ian et al. (2011) Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections. Nat Rev Microbiol 9:62-75
Vaddady, Pavan K; Lee, Richard E; Meibohm, Bernd (2010) In vitro pharmacokinetic/pharmacodynamic models in anti-infective drug development: focus on TB. Future Med Chem 2:1355-69
Sun, Dianqing; Scherman, Michael S; Jones, Victoria et al. (2009) Discovery, synthesis, and biological evaluation of piperidinol analogs with anti-tuberculosis activity. Bioorg Med Chem 17:3588-94
Budha, Nageshwar R; Lee, Robin B; Hurdle, Julian G et al. (2009) A simple in vitro PK/PD model system to determine time-kill curves of drugs against Mycobacteria. Tuberculosis (Edinb) 89:378-85

Showing the most recent 10 out of 17 publications