Abstract

Pyrazinoic acid esters have been synthesized and found to have greater intrinsic activity against pyrazinamide-susceptible and pyrazinamide-resistant isolates of M. tuberculosis. These compounds have intrinsic activity against M. bovis and M. kansasii, organisms which are resistant to pyrazinamide. The pyrazinoic acid esters and pyrazinamide function as prodrugs of pyrazinoic acids. The former agents require a mycobacterial esterase for activation rather than an amidase which is required by the latter agent. The in vitro and in vivo activity of PAEs will be optimized by modification of both the alcohol and pyrazine moieties. New analogs will be evaluated in vitro and in M. tuberculosis infected murine macrophage cultures. The toxicity and pharmacology of selected PAEs will be studied prior to their evaluation in a murine tuberculosis model. The development of additional agents for,the treatment of tuberculosis is of great importance due to the emergence of multidrug resistant tuberculosis in HIV infected individuals (particularly prisoners and intravenous drug users). Rational structural modification of a well established primary agent such as pyrazinamide has a high likelihood of yielding a new candidate for clinical evaluation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033690-02
Application #
3148736
Study Section
Special Emphasis Panel (SRC (59))
Project Start
1992-09-30
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Central New York Research Corporation
Department
Type
DUNS #
606310928
City
Syracuse
State
NY
Country
United States
Zip Code
13210