Tuberculosis (TB) is the second leading cause of death world wide due to an infectious agent. Mycobacterium tuberculosis (Mtb) is a rod-shaped bacillus, which causes this contagious disease. TB is estimated to infect one-third of the world's population. Due to increasing drug resistance and issues arising from HIV/TB co-infection, there is a significant need for new medications. One attractive target for drug design is the non-mevalonate pathway (NMP) of isoprene biosynthesis. The first enzyme of this pathway, 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr) has been the focus of recent efforts to find novel antitubercular agents. Natural product FR33289, an analog of antibiotic FR900098, inhibits Dxr from Plasmodium falciparum, the causative agent of malaria. We are interested in assessing the inhibition of Mtb Dxr by FR33289 and other �-substituted analogs. Here, we describe new synthetic routes to obtain FR33289 and related analogs as well as the evaluation of these compounds against Mtb and Mtb Dxr.                                                         

Synthesis of natural product FR33289 and analogs targeting inhibition of Mtb Dxr

248th National Meeting (2014)

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