The SAR of the three series clearly indicates that the nature of cationic substituents and their position is important in deciding the anti-trypanosomal activity of benzofuran derivatives. The introduction of phenoxy fragment into a benzofuran structural motif may result into retention of affinity for the aminopurine P2 transporter, which could be the reason for anti-trypanospomal activity of benzofuran derivatives. However the precise mechanism by which these compounds show their anti-trypanosomal activity in not known. Among the three series the 2-phenylbenzofuran derivatives are attractive molecules because of their high activity, low cytotoxicity and high selectivity against the HAT parasite. The introduction of phenoxy fragment into the aromatic ring protects the phenylbenzofuran dervatives from metabolic deactivation. This structural modification retains affinity for the aminopurine P2 transporter. The diamidine and the hydroxy or methoxy group may be involved in binding to the DNA minor groove. Thus multiple modes of action may be the reason for promising anti-trypanosomal propertries of 2-phenylbenzofuran derivatives. Thus these compounds require further assessment in order to develop as newer antitrypanosomal agents with promising pharmacokinetic profile.