Synthesis and in vitro and in vivo evaluation of antimalarial polyamines

• A library of diamido polyamines has been synthesized.
• Library comprised of benzamide, phenylacetamide and 3-phenylpropanamide analogues.
• Potent in vitro antimalarial activity observed for selected analogues.
• One analogue demonstrated modest in vivo activity.

We recently reported that 1,14-diphenylacetamide derivatives of spermine exhibit potent nM in vitro growth inhibition properties of Plasmodium falciparum. In an effort to expand the structure–activity relationship of this compound class towards malaria, we have prepared and biologically tested a library that includes benzamide and 3-phenylpropanamide ‘capping acid’ groups, and polyamines that include spermine (PA3-4-3) and chain extended analogues PA3-8-3 and PA3-12-3. 2-Hydroxy and 2,5-dimethoxy analogues were typically found to exhibit the most potent activity towards the dual drug resistant strain K1 of P. falciparum with IC50's in the range of 1.3–9.5 nM, and selectivity indices (SI) of 42,300 to 4880. In vivo evaluation of three analogues against Plasmodium berghei was undertaken, with one demonstrating a modest 27.9% reduction in parasitaemia.

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