Synthesis and Biological Evaluation of Selective Tubulin Inhibitors As Anti-Trypanosomal Agents

Document Type

Article

Publication Date

1-1-2017

Publication Title

Bioorganic and Medicinal Chemistry

Abstract

African trypanosomiasis is still a threat to human health due to the severe side-effects of current drugs. We identified selective tubulin inhibitors that showed the promise to the treatment of this disease, which was based on the tubulin protein structural difference between mammalian and trypanosome cells. Further lead optimization was performed in the current study to improve the efficiency of the drug candidates. We used Trypanosoma brucei brucei cells as the parasite model, and human normal kidney cells and mouse macrophage cells as the host model to evaluate the compounds. One new analog showed great potency with an IC of 70 nM to inhibit the growth of trypanosome cells and did not affect the viability of mammalian cells. Western blot analyses reveal that the compound decreased tubulin polymerization in T. brucei cells. A detailed structure activity relationship (SAR) was summarized that will be used to guide future lead optimization. 50

DOI

10.1016/j.bmc.2017.04.009

Volume

25

Issue

12

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