Molecular Design
and Synthesis of Ivermectin Hybrids
Targeting Hepatic and Erythrocytic Stages of Plasmodium Parasites
Posted on 2020-02-14 - 15:11
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.
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Singh, Lovepreet; Fontinha, Diana; Francisco, Denise; Mendes, Antonio M.; Prudêncio, Miguel; Singh, Kamaljit (2020). Molecular Design
and Synthesis of Ivermectin Hybrids
Targeting Hepatic and Erythrocytic Stages of Plasmodium Parasites. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.0c00033
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AUTHORS (6)
LS
Lovepreet Singh
DF
Diana Fontinha
DF
Denise Francisco
AM
Antonio M. Mendes
MP
Miguel Prudêncio
KS
Kamaljit Singh
KEYWORDS
blood stage infectionshepaticivermectin antimalarial hybridsblood stage developmentsilico docking analysisPlasmodium falciparum sporogonicimpairs Plasmodium berghei developmentAnopheles stephensi mosquitoesPlasmodium Parasites Ivermectininsecticidal effectIvermectin Hybrids Targeting Hepaticmalaria control strategiesglutamate-gated chloride channels