Abstract
Plasmodium falciparum’s resistance to available antimalarial drugs highlights the need for the development of novel drugs. Pyrimidine de novo biosynthesis is a validated drug target for the prevention and treatment of malaria infection. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the oxidation of dihydroorotate to orotate and utilize ubiquinone as an electron acceptor in the fourth step of pyrimidine de novo biosynthesis. PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue. In this study, we screened 40,400 compounds from the Kyoto University chemical library against recombinant PfDHODH. These studies led to the identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine and its derivatives as a new class of PfDHODH inhibitor. Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development.
Highlights
Significant morbidity and mortality caused by protozoan parasitic infection pose serious threats to global health
43 PfDHODH inhibitors identified in this study showed no inhibition against the human enzyme or mammalian mitochondrial complexes I–III and II–III, except for 2, which weakly inhibited complex I–III activity (Table 1)
We have identified PfDHODH inhibitors with new chemical scaffolds that inhibited the growth of the P. falciparum 3D7 strain
Summary
Significant morbidity and mortality caused by protozoan parasitic infection pose serious threats to global health. The development of new antimalarial drugs is needed. The majority of malaria cases reported are caused by Plasmodium falciparum. This parasite has a complex life cycle involving intermediary (human) and definitive (mosquitoes) hosts. Once a human is infected, the sporozoites migrate to the liver, invading hepatocyte (liver stage) and differentiating into schizont-containing hepatic merozoites. The hepatic schizonts burst and release merozoites, which infect red blood cells. Parasites undergo consecutive asexual development to ring, trophozoite, and schizont stages. Mature schizonts release merozoites into the bloodstream and initiate another replication cycle. A small fraction of parasites infecting erythrocytes undergo sexual development into female and male gametocytes, which are transmitted by mosquitoes during a blood meal
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