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 IC 50 '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.