School of Medical Sciences


Medicinal Chemistry - development of novel drugs for the treatment of tuberculosi

Group leader


bacteria

Tuberculosis (TB) is a bacterial infection that is re-emerging as a world health emergency, due in part to its co-occurrence with HIV infection, and the development of treatment-resistant strains of the bacterium. It is estimated that one third of the world’s population is infected with the latent form of TB; of these, each year 9 million people will develop the active, contagious form of the disease, and of these 2-3 million will die from their infection. The current treatment for TB requires that a cocktail of antibiotic drugs be taken continuously for at least six months. There is an urgent need for more active, shorter regimen treatments for TB, particularly against the dormant and drug-resistant forms.

PA-840

The New York-based Global Alliance for TB Drug Development (GATB) is currently sponsoring a clinical trial of the first radically different anti-TB drug to be developed in 40 years, known as PA-824. PA-824 is particularly active against the dormant stages of TB and it began phase 2 trials in human volunteers in 2008.


Global Alliance for TB Drug Development

Current research


  • Our group was awarded funding from the GATB to develop second-generation analogues of PA-824, seeking to establish more potent activity and an improved pharmacokinetic profile. The Auckland chemistry team, based at the Auckland Cancer Society Research Centre, comprises five medicinal chemists who have to date prepared nearly 1000 compounds for evaluation against cultures of the TB bacterium. Many highly active compounds have now been identified, the most promising of which have been prepared in sufficient quantities to enable their evaluation in mouse models of TB. The selection of a number of compounds which have significantly better activity than PA-824 for advanced in vivo evaluations is almost complete, after which the chemistry efforts on the project will focus on providing larger quantities of the drugs required for these studies. The biological evaluation of these compounds is being carried out by Professor Scott Franzblau and his team at the Institute for Tuberculosis Research, University of Illinois at Chicago.
  • The activity of PA-824 and its analogues is believed to result from their metabolic activation within the bacterium. In a collaboration with Associate Professor Bob Anderson's group in the Chemistry Department, investigations of the novel reductive chemistry of PA-824 and its analogues are underway, to better understand the mode of action of this new class of prodrugs.
  • A major problem arising from the chemotherapy of most infectious diseases is the development of resistance to the treatment drugs. This is certainly the case for TB, where the appearance of multidrug resistant (MDR) and more recently, extensively drug resistant (XDR) forms of TB is now well documented. The development of drug resistance can typically be reduced by the administration of a cocktail of antibacterial drugs which have different mechanisms of action. An alternative and relatively novel approach to overcoming the development of drug resistance is to design multifunctional drugs, which combine the key features of several active agents within the one drug molecule. Such compounds would ideally attack several drug targets in the bacterium simultaneously. These molecules could ultimately prove to be more active than the component drugs alone, and have the potential to simplify and shorten drug therapy. The GATB has recently awarded new funding to the Auckland group to develop such hybrid molecules for the treatment of TB. The biological evaluation of these multifunctional molecules is being carried out by Assistant Professor Anne Lenaerts’ team at Colorado State University.

Recent publications


  • Thompson, A.M., Blaser, A., Anderson, R.F., Shinde, S.S., Franzblau, S.G., Ma, Z., Denny, W.A., Palmer, B.D. Synthesis, reduction potentials and anti-tubercular activity of ring A/B analogues of the bioreductive drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). J. Med. Chem., 2009, 52, 637-645.
  • Anderson, R.F., Shinde, S.S., Maroz, A., Boyd, M., Palmer, B.D., Denny, W.A. Intermediates in the reduction of the antituberculosis drug PA-824, (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine, in aqueous solution. Org. Biomol. Chem., 2008, 6, 1973-1980.

Group members