Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose
Livio Racanè, Lucija Ptiček, Sanja Koštrun, Silvana Raić‐Malić, Martin C. Taylor, Michael J. Delves, Sam Alsford, Francisco Olmo, Amanda Fortes Francisco, John M. Kelly
Abstract
High Resolution Image Download MS PowerPoint Slide 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.