Current treatment options for human African trypanosomiasis (HAT) are ineffective, and they have several well-known clinical limitations. In our continued efforts to identify chemotypes that can be developed into clinically useful drugs, we screened a targeted compound library against the major cathepsin L (rhodesain) in T. brucei. We report the antirhodesain activity and antitrypanosomal activity of the compounds in this letter. The identified compounds can serve as starting points for structure- and/or phenotype-based lead optimization strategy against Trypanosoma brucei.