Structure of two phenylbenzofuran dications with promising anti-trypanosomal activity Tidwell RR et al found that the in vitro anti-trypanosomal activities of bisbenzofuran derivatives against Trypanosoma brucei rhodesiense, and cytotoxicity against mammalian cells depended on the position and the type of cationic substituents as well as the length of the carbon linker between aromatic moieties. As observed in most of the dicationic molecules, the N-substituted congeners were lesser cytotoxic than the unsubstituted diamidines whereas the N-alkylation of cationic fragments reduced the activity of compounds against T. brucei rhodesiense compared to pentamidine. At same time the 5-substituted bisbenzofurans were generally less cytotoxic than compounds bearing substituents in the 4-or 6-positions where as the 4-substituted bisbenzofurans were significantly less active against T. b. rhodesiense than corresponding 5-and 6-substituted isomers. The in vitro activity of the bisbenzofuran series was not so promising and only lead compound 8, (Figure 5b ) exhibited in vitro anti-trypanosomal activity (0.008 µM) comparable to that of pentamidine and melarsoprol. However some compounds from Tidwell series (Figure 7b ) showed reduced cytotoxicity profile compared to pentamidine (for example compound 43 has cytotoxicity of 1.85 µM), but had very poor selectivity profile. Thus was proved that the selectivity of bisbenzofurans against T. b. rhodesiense decreases as number of methylene groups in the alkyl bridge increases.