Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose

We designed and synthesized a series of symmetric bis-6-amidino-benzothiazole
derivatives with aliphatic central units and evaluated their efficacy
against bloodstream forms of the African trypanosome Trypanosoma brucei. Of these, a dicationic benzothiazole
compound (9a) exhibited sub-nanomolar in vitro potency
with remarkable selectivity over mammalian cells (>26,000-fold).
Unsubstituted
5-amidine groups and a cyclohexyl spacer were the crucial determinants
of trypanocidal activity. In all cases, mice treated with a single
dose of 20 mg kg–1 were cured of stage 1 trypanosomiasis.
The compound displayed a favorable in vitro ADME profile, with the
exception of low membrane permeability. However, we found evidence
that uptake by T. brucei is mediated
by endocytosis, a process that results in lysosomal sequestration.
The compound was also active in low nanomolar concentrations against
cultured asexual forms of the malaria parasite Plasmodium
falciparum. Therefore, 9a has exquisite
cross-species efficacy and represents a lead compound with considerable
therapeutic potential.