Growth inhibition of drug-resistant species of Plasmodium falciparum by domain structured N1,N2-derivatized hydrazines: denticity effects, redox switches, and reductant-driven redox-cycling.
Six analogs of bidentate 1-[pyridoxylidene]-2-phenyl]hydrazine, twelve analogs of N2O-tridentate 1-[pyridoxylidene]-2-[heteroaryl]hydrazine, and four O2N-tridentate analogs of 1-[pyridoxylidene]-2-[heteroaroyl] hydrazines were synthesized and characterized. Their solutions in water and DMSO were assayed in vitro for activity against a chloroquine-resistant species of P. falciparum obtained from Hadassah Hospital Blood Bank in Jerusalem. The O2N-tridentate group was essentially inactive, whereas the bidentate group, with N and O liganding atoms, exhibited slight activity against late-stage trophozoites and schizonts of P. falciparum. The N2O-tridentate group, by contrast, was remarkably active against resistant P. falciparum, highlighting the importance of the Denticity Effect in this system. It is assumed that the pyridoxal-based chelator acts as an iron redox mediator, controlling the first coordination sphere and, therefore, the immediate chemical environment of the iron. Chelation of iron-(II) presumably facilitates its oxidation..The Fe(II) --> Fe(III) intra-electron transfer, may be viewed as a switch ("redox switch"), controlling the thermodynamic stability and kinetic lability of the coordination shell. The redox-switch is accompanied by the appearance of a carbon-based Fe-(III)-chelate radical, capable of donating its free electron to the parasite-DNA, thus causing death. The antimalarial N2O-tridentate Fe(III)-chelates appear to be prone to redox-switch, and tend to be converted into their Fe(II) species, whereas the inactive O2N-tridentate analogs apparently cannot do so.
Sarel
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Department of Medicinal Chemistry, The Hebrew University of Jerusalem, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. sarel@cc.huji.ac.il
Iheanacho
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Avramovici-Grisaru
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D000818:Animals; D003500:Cyclization; D004351:Drug Resistance; D004583:Electrons; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007501:Iron / Q000737:chemistry; D008024:Ligands; D015394:Molecular Structure; D010084:Oxidation-Reduction; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development*; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D006834:Hydrazines; D008024:Ligands; D007501:Iron