Description:
<jats:title>ABSTRACT</jats:title>
<jats:p>
It is widely accepted that the struggle against malaria depends on the development of new strategies to fight infection. The “magic bullet” thought to be necessary to reach eradication should not only provide treatment for all
<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium</jats:named-content>
spp. that infect human red blood cells but should also eliminate the replicative and dormant liver forms of the parasite. Moreover, these goals should ideally be achieved by using different mechanisms of action so as to avoid the development of resistance. To that end, two hybrid molecules with covalently linked primaquine and artemisinin moieties were synthesized, and their effectiveness against the liver and blood stages of infection was compared
<jats:italic>in vitro</jats:italic>
and
<jats:italic>in vivo</jats:italic>
with those of the parent compounds. Both hybrids displayed enhanced
<jats:italic>in vitro</jats:italic>
activities, relative to those of the parent compounds, against
<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium berghei</jats:named-content>
liver stages. Both compounds were about as potent as artemisinin against cultured
<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium falciparum</jats:named-content>
(50% inhibitory concentration [IC
<jats:sub>50</jats:sub>
], ∼10 nM). When used to treat a murine
<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. berghei</jats:named-content>
infection, one of the molecules displayed better efficacy than an equimolar mixture of the parent pharmacophores, leading to improved cure and survival rates. These results reveal a novel approach to the design and evaluation of antimalarials based on the covalent combination of molecules acting on different stages of the parasite life cycle.
</jats:p>