Molecular Design and Synthesis of Ivermectin Hybrids Targeting Hepatic and Erythrocytic Stages of Plasmodium Parasites

Ivermectin
is a powerful endectocide, which reduces the incidence
of vector-borne diseases. Besides its strong insecticidal effect on
mosquito vectors of the disease, ivermectin inhibits Plasmodium falciparum sporogonic and blood stage
development and impairs Plasmodium berghei development inside hepatocytes, both in vitro and in vivo. Herein,
we present the first report on structural modification of ivermectin
to produce dual-action molecular hybrids with good structure-dependent
in vitro activity against both the hepatic and erythrocytic stages
of P. berghei and P.
falciparum infection, suggesting inclusion of ivermectin
antimalarial hybrids in malaria control strategies. The most active
hybrid displayed over threefold and 10-fold higher in vitro activity
than ivermectin against hepatic and blood stage infections, respectively.
Although an overwhelming insecticidal effect against Anopheles stephensi mosquitoes in laboratory conditions
was not noticed, in silico docking analysis supports allosteric binding
to glutamate-gated chloride channels similar to ivermectin.