S. Sarel, E. N. Iheanacho and S. Avramovici-Grisaru Pages 159 - 171 ( 13 )
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) (r) 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 carbonbased 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.
growth-Inhibition, drug-resistant plasmodium falciparum, pyridoxal-based chelators, parasitemia by 3hhypoxantin incorporation, electronic effects, denticity effects, redox-cycling
Department of Medicinal Chemistry, The Hebrew University of Jerusalem, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.