An in-vitro model to assess effectiveness of carbazoles for treating human African Trypanosomiasis in a mouse model of disease

Human African Trypanosomiasis (HAT) is a neglected tropical disease caused by the microbial eukaryote Trypanosoma brucei. If left untreated, HAT is fatal. Current medications for T.brucei infection are difficult to administer or can cause undesirable side effects. It is important to develop new drugs to treat HAT because over time T.brucei can become resistant to chemotherapy. Our laboratory is optimizing new leads for anti-trypanosomiasis chemotherapy. We showed earlier that the carbazole CBL0137 cures HAT in a mouse model of disease, and in modes of action studies, inhibits mitosis and endocytosis of transferrin in T. brucei. Here we evaluated structurally similar compounds, CBL0174 and CBL0187, against T. brucei. Mitochondrial DNA is found in a single nucleoid termed the kinetoplast in T. brucei. At different stages of the cell cycle, T. brucei have different numbers of nuclei and kinetoplasts. Mitosis is indicated by the presence of two nuclei and two kinetoplasts per trypanosome. We established previously that in vitro proliferation inhibition studies do not accurately predict how compounds would affect T. brucei in a mouse infection. So, we are developing a pharmacodynamic/pharmacokinetic model to predict the effectiveness of drugs in mice. A pharmacokinetics study was performed in mice to obtain AUC and Cmax values. When cells were treated with that AUC0-6h concentration of CBL0137, CBL0174, and CBL0187 mitosis in trypanosomes was inhibited by all three carbazoles. However, only CBL0137 blocked endocytosis of transferrin. We intend to continue using this methodology to discover new lead drugs for HAT.