Syntheses of benzothiazole amidoximes and arylimidamides and evaluation of their ADME and DNA binding properties and activity against Trypanosoma brucei

Novel 6-amidoxime- and 6-arylimidamide-substituted benzothiazoles were synthesised to investigate their activity against Trypanosoma brucei, the causative agent of African trypanosomiasis. Benzothiazole amidoxime 12b, with diethylaminoethyl and fluorine substituents on a phenoxymethylene linker exhibited pronounced (IC<inf>50</inf> = 0.92 μM) and selective (SI = 18) antitrypanosomal activity. ADME profiling showed that the majority of compounds synthesised are metabolically stable and that arylimidamides have low membrane permeability, while amidoximes, including 12b, have moderate to high permeability. Binding assays indicate that amidoxime 12b binds to DNA/RNA by intercalation, whereas arylimidamide 29b displays groove binding. 12b was found to be a substrate of the P-glycoprotein efflux pump, a factor that may have limited its activity in a murine model of infection, despite the other favourable properties. Structural diversification of aryl-substituted motif in amidoxime benzothiazole series will be explored to further optimize activity and ADME properties, and to overcome issues associated with low membrane permeability.