Antiplasmodial and Insecticidal Activities of Third-Generation Ivermectin Hybrids

Preclinical and/or clinical studies have demonstrated
the potential
of Ivermectin (IVM) for malaria control. In order to improve its antiplasmodial
activity and build on previous knowledge, we have designed a third
generation of hybrid molecules in which selected pharmacophores were
appended to the IVM macrolide, while retaining one or both sugar moieties
at the C-13 position. Moreover, we synthesized IVM hybrids that contain
structural features of potent IVM metabolites. The evaluation of the in vitro antiplasmodial activity of these compounds against Plasmodium berghei pre-erythrocytic stages and Plasmodium falciparum erythrocytic stages identified
molecules that displayed enhanced activity against the latter when
compared to IVM. Additionally, two IVM intermediates and one IVM hybrid
retained the insecticidal activity of the parental molecule, clarifying
the contribution of the sugar moieties to this feature. Altogether,
these results provide key structure–activity relationships
to guide the rational design of new generations of IVM hybrids.