Abstract
Drug repositioning offers an effective alternative to
drug design to tackle the urgent need for novel antimalarial treatments. The antiamoebic compound emetine dihydrochloride has been identified as a potent
inhibitor of the multidrug-resistant strain K1 of
(50% inhibitory concentration [IC
], 47 nM ± 2.1 nM [mean ± standard deviation]). Dehydroemetine, a synthetic analogue of emetine dihydrochloride, has been reported to have less-cardiotoxic effects than emetine. The structures of two diastereomers of dehydroemetine were modeled on the published emetine binding site on the cryo-electron microscopy (cryo-EM) structure with PDB code 3J7A (
80S ribosome in complex with emetine), and it was found that (-)-
,
-dehydroemetine mimicked the bound pose of emetine more closely than did (-)-
,
-dehydroisoemetine. (-)-
,
-dehydroemetine (IC
71.03 ± 6.1 nM) was also found to be highly potent against the multidrug-resistant K1 strain of
compared with (-)-
,
-dehydroisoemetine (IC
, 2.07 ± 0.26 μM), which loses its potency due to the change of configuration at C-1'. In addition to its effect on the asexual erythrocytic stages of
, the compound exhibited gametocidal properties with no cross-resistance against any of the multidrug-resistant strains tested. Drug interaction studies showed (-)-
,
-dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride and (-)-
,
-dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity affecting the mitochondrial membrane potential, indicating a possible multimodal mechanism of action.