DFMO [70] [71] [72] is the most recently developed agent for late stage T. b. gambiense and T. b. brucei sleeping sickness, but has not been active against all strains of T. b. rhodesiense. The major drawbacks of DFMO are its cost, the duration of treatment and its availability. Recent clinical studies have investigated that DMFO can be used in combination with clinically used trypanocides including suramin, nifurtimox and melarsoprol [73, 74] . These combinations result in significant reduction in DFMO dosage and time of administration. Initial clinical study has shown that DFMO + nifurtimox are superior to DFMO + melarsoprol and melarsoprol + nifurtimox. The DFMO + nifurtimox regimen (NECT regimen) allowed reduction in DFMO regimen from 14 to 7 days (56 versus 28 infusions) with a 94% cure rate and are associated with significantly reduced adverse side effects as compared to melarsoprol-based therapy. The success of the combined regimen has been most likely due to ability of DMFO to reduce trypanothione levels and resistance to oxidative stress and the ability of nifurtimox to generate oxidative stress. Recently Gilbert et al [76] designed, synthesized, and evaluated substituted polyamines, carrying 1,3,5-triazine units, as potential anti-trypanosomal drugs. Preliminary results indicated that this route might be successful, and lead structure A (Figure 26 ) was used as a starting point for the synthesis of two series of analogues. In the first series, the influence of structural changes of the central core unit was investigated while in the second series, the effect of additional methyl substituents on the 1,3,5-triazine was studied. The compounds were designed with the intention to selectively target the interior of T. brucei via the P2 amino-purine transporter. In the first series the compound containing the ndodecyl chain as core unit, showed weak activity against T. b. rhodesiense. The compound with n-nonyl chain was the most promising compound and its various analogues were designed by replacing NH 2 groups on the triazine ring with NHMe and NMe 2 groups. Introduction of one or two methyl groups per triazine unit resulted in a 10fold increase in anti-trypanosomal activity. When four methyl groups per triazine unit were introduced, an 80-fold increase in activity was observed. Similarly, replacement of NH 2 group in n-dodecyl chain led to 2-20-fold higher anti-trypanosomal activity for the methylated derivatives. Monosubstituted compounds showed a slight increase in activity against T. b. rhodesiense as compared to the disubstituted compounds. The methylamino substituted triazines attached to the C9-(compound 8c, Figure 27 ) or C12-(compound 8f, Figure 27 ) polyamine precursor via an additional CH 2 linker resulted in most active trypanocidal compounds(IC 50 of 8c = 0.27µM and 8f = 0.18 µM). Beside good activity, the compounds showed poor in vivo activity producing no cure to the infected mice and concentrations greater than 10 mg kg −1 induced severe acute toxicity. The actual mode of action for the reported triazine substituted polyamines remains unclear. So to understand and improve the activities of these compounds, further research has to verify intracellular drug targets and possible metabolic pathways.