New treatment option for second stage African sleeping sickness: In vitro and in vivo efficacy of aza analogs of DB289

African sleeping sickness is a fatal parasitic disease and all drugs currently in use for treatment have strong liabilities. It is essential to find new, effective and less toxic drugs ideally with oral application to control the disease. In this study, the aromatic diamidine DB75 (furamidine), two aza analogs DB820 and DB829 (CPD-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites were evaluated against African trypanosomes. The active parent diamidines did show similar in vitro profiles against different Trypanosoma brucei strains, melarsoprol and pentamidine resistant lines and against a P2 transporter knockout strain (AT1KO), with DB75 as the most trypanocidal molecule. In the T. b. rhodesiense STIB900 acute mouse model, the aza analogs DB820 and DB829 demonstrated superior activity over DB7The aza prodrugs DB844 and DB868 as well as two metabolites of DB844 were orally more potent in the T. b. brucei GVR35 CNS mouse model than DB289 (pafuramidine maleate). Unexpectedly, the parent diamidine DB829 showed high activity in the CNS mouse model by the intraperitoneal route. In conclusion, DB868 with oral or DB829 with parenteral application are potential candidates for further development for a 2(nd) stage African sleeping sickness drug