pKa modulation of a bis(2-aminoimidazoline) DNA minor groove binder that targets the kinetoplast of Trypanosoma brucei

The parasite Trypanosoma brucei, ethiologic agent of human African trypanosomiasis (i.e. sleeping sickness), contains a kinetoplast with the mitochondrial DNA (kDNA) comprising of >70 % AT base pairs. Hence, DNA minor groove binding molecules have been investigated as antitrypanosomal agents. Diphenyl-based bis(2-iminoimidazolidines) are promising DNA minor groove binders that are curative in mouse models of stage 1 trypanosomiasis but devoid of activity in the late(CNS)-stage disease, possibly due to poor brain penetration caused by their dicationic nature. As a strategy to reduce the pKa of the basic 2-iminoimidazolidine groups, halogen atoms (R1 = Cl, F) were introduced in the structure of lead compound 1 and the pKa of the new compounds was determined . A reduction of 1–2 pKa units for the imidazolidine group linked to the substituted phenyl ring was observed. In vitro activities (EC50) against wild type and resistant strains of T. b. brucei were in the submicromolar range with four compounds being more active and selective than 1 (SI > 340).1 The chloro-substituted derivative 5a, which was curative in vivo in a mouse model of stage 1 infection by T. b. rhodesiense, appeared as a new promising lead compound.2 Mechanistic studies were performed to identify the cellular target of these dicationic compounds. Altogether, our results show that 1 and 5a share the same mechanism of action against T. brucei, acting specifically on the integrity of the kinetoplast by altering the structure and replication of kDNA.2