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Objectives  There is an urgent need to develop a safe, effective, orally active, and inexpensive therapy for African trypanosomiasis due to the drawbacks of current drugs. Selective tubulin inhibitors have the potential to be promising drug candidates for the treatment of this disease, which is based on the tubulin protein structural difference between mammalian and trypanosome cells. We propose to identify novel tubulin inhibitors from a compound library developed based on the lead compounds that selectively target trypanosomiasis.    Methods  We used  Trypanosoma brucei brucei  as the parasite model, and human normal kidney cells and mouse microphage cells as the host model. Growth rates of both trypanosomes and mammalian cells were determined as a means to screen compounds that selectively inhibit the proliferation of parasites. Furthermore, we examined the cell cycle profile of the parasite and compared tubulin polymerization dynamics before and after the treatment using identified compounds. Last,  in vivo  anti-parasite activities of these compounds were determined in  T .  brucei -infected mice.    Results  Three compounds were selected that are 100 fold more effective against the growth of  T .  brucei  cells than mammalian cells. These compounds caused cell cycle progression defects in  T .  brucei  cells. Western analyses indicated that these compounds decreased tubulin polymerization in  T .  brucei  cells. The  in vivo  investigation revealed that these compounds, when admitted orally, inhibited  T .  brucei  cell proliferation in mouse blood. However, they were not potent enough to clear up the infection completely.    Conclusions  These compounds are promising lead compounds as orally active agents for drug development of anti-trypanosome agents. A more detail structure activity relationship (SAR) was summarized that will be used to guide future lead optimization to improve the selectivity and potency of the current compounds.

Orally Active and Selective Tubulin Inhibitors as Anti-Trypanosome Agents