Nifurtimox, a hydrazone of 5-nitro-2-furaldehyde is used therapeutically against Trypanosoma brucei and Trypanosoma cruzi infections. Exploiting our previous observation that adamantane derivatives display trypanocidal activity, we designed and synthesised a range of hydrazones of 5-nitro-2-furaldehyde with adamantane alkanohydrazides. The most promising compounds had >20 times greater activity (IC50 ∼ 100 nM) than nifurtimox, with selectivity indices of 20–80. SAR studies revealed that activity is associated with increased lipophilicity and influenced by conformational flexibility. Derivatives lacking a nitro group were practically inactive against both parasites. The approaches described demonstrate the feasibility of enhancing the potency of chemical entities with known trypanocidal activity.