Development of nitrofuranylamides as antituberculosis agents

MEDI 312

Richard E Lee, relee@utmem.edu1, Rajendra P Tangallapally, rtangallapal@utmem.edu2, Raghunandan Yendapally, ryendapa@utmem.edu2, Robin E.B. Lee1, AnTawan J. Daniels1, and Kirk Hevener1. (1) Department of Pharmaceutical Sciences, University of Tennessee HSC, 847 Monroe Ave Rm327, Memphis, TN 38163, (2) Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, 847 Monroe Ave Rm327, Memphis, TN 38163
There is an urgent need to develop fast-acting, potent, new anti-tuberculosis agents active against multi-drug resistant strains of tuberculosis. In an effort to discover new inhibitors of mycobacterial cell wall biosynthesis, a nitrofuranyl amide was discovered with good anti-tuberculosis activity and good lead like properties. After extensive optimization and development of a detailed structure activity relationship the primary target was found to be in flavin metabolism rather than cell wall biosynthesis. The development of this nitrofuranyl amide series will be presented including: SAR developed, including a CoMFA study; the microbiological assessment against sensitive and multi-drug resistant strains; in vitro and in vivo data for lead compounds in the series. Lessons learned in the development of new anti-tuberculosis agents and strategies used to modify compounds with good in vitro activity to achieve good in vivo activity will also be highlighted.
 

Drug Resistant Tuberculosis
1:30 PM-4:35 PM, Wednesday, 16 March 2005 Convention Center -- Room 6C, Oral

Division of Medicinal Chemistry

The 229th ACS National Meeting, in San Diego, CA, March 13-17, 2005