Hit-to-Lead Optimization of Benzoxazepinoindazoles As Human African Trypanosomiasis Therapeutics

Human African trypanosomiasis (HAT) is a neglected tropical
disease
caused by infection with either of two subspecies of the parasite Trypanosoma brucei. Due to a lack of economic incentive
to develop new drugs, current treatments have severe limitations in
terms of safety, efficacy, and ease of administration. In an effort
to develop new HAT therapeutics, we report the structure–activity
relationships around T. brucei for a series of benzoxazepinoindazoles
previously identified through a high-throughput screen of human kinase
inhibitors, and the subsequent in vivo experiments
for HAT. We identified compound 18, which showed an improved
kinase selectivity profile and acceptable pharmacokinetic parameters,
as a promising lead. Although treatment with 18 cured
60% of mice in a systemic model of HAT, the compound was unable to
clear parasitemia in a CNS model of the disease. We also report the
results of cross-screening these compounds against T. cruzi, L. donovani, and S. mansoni.