pK_a 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 pK_a of the basic 2-iminoimidazolidine groups, halogen atoms (R₁ = Cl, F) were introduced in the structure of lead compound 1 and the pK_a of the new compounds was determined . A reduction of 1–2 pK_a 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