epoxyazadiradione and Malaria

Epoxyazadiradione (1), a major compound derived from Neem oil, showed modest anti-plasmodial activity against CQ-resistant and CQ-sensitive strains of the most virulent human malaria parasite P. falciparum. A series of analogues were synthesized by modification of the key structural moieties of this high yield natural product. Out of the library of all compounds tested, compounds 3c and 3g have showed modest anti-plasmodial activity against CQ-sensitive (IC

Topics: Animals; Antimalarials; Antineoplastic Agents; Azadirachta; Cell Line, Tumor; Cell Proliferation; Humans; Limonins; Malaria; Malaria, Falciparum; Mice; Mice, Inbred BALB C; Neoplasms; Plasmodium berghei; Plasmodium falciparum

The Plasmodium falciparum orthologue of the human cytokine, macrophage migratory inhibitory factor (PfMIF), is produced by the parasite during malaria infection and modulates the host's immune response. As for other MIF orthologues, PfMIF has tautomerase activity, whose inhibition may influence the cytokine activity. To identify small-molecule inhibitors of the tautomerase activity of PfMIF, virtual screening has been performed by docking 2.1 million compounds into the enzymatic site. Assaying of 17 compounds identified four as active. Substructure search for the most potent of these compounds, a 4-phenoxypyridine analogue, identified four additional compounds that were purchased and also shown to be active. Thirty-one additional analogues were then designed, synthesized, and assayed. Three were found to be potent PfMIF tautomerase inhibitors with K(i) of ∼40 nM; they are also highly selective with K(i) > 100 μM for human MIF.

Topics: Antimalarials; High-Throughput Screening Assays; Humans; Hydrogen Bonding; Isomerases; Macrophage Migration-Inhibitory Factors; Malaria; Models, Molecular; Molecular Structure; Plasmodium falciparum; Protein Binding; Protozoan Proteins; Small Molecule Libraries; Structure-Activity Relationship