Increased efficacies of pyridyl analogues of 2,5-bis(4-amidinophenoxy)furan (furamidine) [25] [26] [27] encouraged Tidwell RR et al [28] to synthesize pentamidine analogues in which the phenyl rings of pentamidine were replaced with pyridyl fragments. This replacement resulted in series of 18 compounds (Figure 4a ), most of which had lower cytotoxicity than pentamidine. SAR study pointed out that the antiprotozoal properties of these compounds depended on the placement of cationic moieties on the pyridine rings as well as the nature of substituents on the amidine groups. The N-substituted congeners were lesser cytotoxic than the unsubstituted diamidines whereas the N-alkylation of cationic fragments reduces the activity of compounds against T. brucei rhodesiense compared to pentamidine. A same trend was observed in pentamidine analogues series. The 2, 6-substituted dications (compounds 11-13, figure 4a ) and 2,4-substituted dications (compounds 14-18, figure 4a ) displayed lower potencies against T. brucei rhodesiense than the corresponding 2,5-substituted isomers (compounds 1-10, figure 4a), while among the 2, 5-substituted dications, the compounds possessing cationic substituents adjacent to nitrogen atoms in pyridine rings displayed superior activities against parasites compared to pentamidine as evident from compound 6 (figure 4b) which showed promising anti-trypanosomal activity (0.001µM) and lower cytotoxicity (4.90µM) than pentamidine and melarsoprol, but had poor in vivo activity giving only 1/4 cures in the STIB900 mouse model. However diamidoxime compound 9 (Figure 4c ), an oral prodrug of diamidine compound 6 ( Figure  4b ), exhibited excellent in vivo activity curing four out of four animals upon oral administration in STIB900 mouse model. Although compound 9 did not provide cure in the CNS mouse model of infection but its BBB permeability could potentially be improved by developing prodrug using lipophillic substitutions in place of hydrophilic substitution as used in compound 9. This could provide higher concentration of compound 6 in CNS.