Molecular Design and Synthesis of Ivermectin Hybrids Targeting Hepatic and Erythrocytic Stages of <i>Plasmodium</i> Parasites

Abstract

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 <i>Plasmodium falciparum</i> sporogonic and blood stage development and impairs <i>Plasmodium berghei</i> 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 <i>P. berghei</i> and <i>P. falciparum</i> 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 <i>Anopheles stephensi</i> mosquitoes in laboratory conditions was not noticed, in silico docking analysis supports allosteric binding to glutamate-gated chloride channels similar to ivermectin.