| Human African Trypanosomiasis (HAT), also known as sleeping sickness, afflicts hundreds of thousands of individuals in sub-Saharan Africa with another 60 million people at risk of infection. The agents that are currently available as anti-trypanosomals are generally unsatisfactory due to a combination of their low efficacy, dangerous side effects and difficulty in administration. Although drug development efforts have recently been focused on creating less toxic, more potent O-methyl amidoxime prodrugs with an orally bioavailable formulation, the overall mechanism of action of this series of compounds is unknown.;The focus of this research is to identify novel metabolites of the O-methyl amidoxime prodrugs, investigate the apoptotic effects by the prodrug and each metabolite, and the inhibitory effect to the metabolizing CYP1 enzymes. These results may help us to better understand the mechanism of actions and mechanism of toxicity of the anti-trypanosomal O-methyl amidoxime prodrugs, and therefore facilitate the further drug development in the future. |
