Human Africantrypanosomiasis and leishmaniasis are neglected diseases primarily affecting impoverished nations and are caused by trypanosomatid protozoans.  Both diseases are in need of new treatments, but such improvements have been hindered by the high cost of drug discovery and development and the lack of economic incentive to develop new drugs.  The repurposing of known pharmaceuticals for treatment of trypanosomal infections can speed up the process of new drug discovery.  The trypanosomatids  Trypanosoma brucei and Leishmania major possess multiple target of rapamycin (TOR) enzymes that are essential for cell growth and virulence.  The mammalian homolog, mTOR, has been the focus of many industrial drug discovery programs for the treatment of cancer.  Thus, there is a rich medicinal chemistry history associated with mTOR with many details regarding optimal chemical matter.  These known mTOR inhibitor chemotypes can be repurposed to develop lead compounds for trypanosomiasis and  leishmaniasis.  Presented herein are the selection and initial screening results of a handful of commercially available mTOR inhibitors against T. brucei and L. major as well as the design and synthesis of a variety of analogs of two of these mTOR inhibitors, PI-103 and WYE-354.

Trypanosomal target of rapamycin: Repurposing of mammalian TOR inhibitors for neglected disease drug discovery

240th National Meeting (2010)

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