thiosemicarbazide and Hemolysis

Iron chelators inhibit the growth of the malaria parasite, Plasmodium falciparum, in culture and in animal and human studies. We previously reported the anti-plasmodial activity of the chelators, 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), 2-hydroxy-1-naphthylaldehyde 4-methyl-3-thiosemicarbazone (N4mT), and 2-hydroxy-1-naphthylaldehyde 4-phenyl-3-thiosemicarbazone (N4pT). In fact, these ligands showed greater growth inhibition of chloroquine-sensitive (3D7) and chloroquine-resistant (7G8) strains of P. falciparum in culture compared to desferrioxamine (DFO). The present study examined the effects of 311, N4mT and N4pT on erythrocyte membrane integrity and asexual parasite development. While the characteristic biconcave disk shape of the erythrocytes was unaffected, the chelators caused very slight hemolysis at IC50 values that inhibited parasite growth. The chelators 311, N4mT and N4pT affected all stages of the intra-erythrocytic development cycle (IDC) of P. falciparum in culture. However, while these ligands primarily affected the ring-stage, DFO inhibited primarily trophozoite and schizont-stages. Ring, trophozoite and schizont-stages of the IDC were inhibited by significantly lower concentrations of 311, N4mT, and N4pT (IC50=4.45±1.70, 10.30±4.40, and 3.64±2.00μM, respectively) than DFO (IC50=23.43±3.40μM). Complexation of 311, N4mT and N4pT with iron reduced their anti-plasmodial activity. Estimation of the intracellular labile iron pool (LIP) in erythrocytes showed that the chelation efficacy of 311, N4mT and N4pT corresponded to their anti-plasmodial activities, suggesting that the LIP may be a potential source of non-heme iron for parasite metabolism within the erythrocyte. This study has implications for malaria chemotherapy that specifically disrupts parasite iron utilization.

Topics: Antimalarials; Erythrocyte Membrane; Hemolysis; Humans; Hydrazones; Iron Chelating Agents; Plasmodium falciparum; Semicarbazides

Cr(III), Mn(II) and Fe(III) complexes derived from the quadruple potential dithione heterocyclic thiosemicarbazide ligand (H(2)PET) have been prepared and characterized by conventional techniques. The isolated complexes were assigned the formulae, [Cr(HPET)(H(2)O)(2)Cl(2)]·3H(2)O, [Mn(HPET)(H(2)O)Cl](2) and [Fe(HPET)(H(2)O)(2)Cl(2)]·H(2)O, respectively. IR data revealed that the ligand behaves as monobasic bidentate through (C=N)(py) and (C-S) groups in both Cr(III) and Fe(III) complexes. In the binuclear Mn(II) complex, H(2)PET acts as NSNS monobasic tetradente via (C=N)(py), (C-S), (C=S) and the new azomethine, (N=C)(*) groups. An octahedral geometry for all complexes was proposed. The bond lengths, bond angles, HOMO, LUMO and dipole moment have been calculated by DFT using materials studio program to confirm the geometry of H(2)PET and its metal complexes. The ligand association constant and the stability constants of its complexes in addition to the thermodynamic parameters were calculated from pH metrically at 298, 308 and 318°K in 50% dioxane-water mixture, respectively. Also, the kinetic and thermodynamic parameters for the different thermal degradation steps of the complexes were determined by Coats-Redfern and Horowitz-Metzger methods. Moreover, the anti-oxidant (using ABTS and DPPH methods), anti-hemolytic, and cytotoxic activities of the compounds have been tested.

Topics: Animals; Antineoplastic Agents; Antioxidants; Carcinoma, Ehrlich Tumor; Chromium; Coordination Complexes; Electron Spin Resonance Spectroscopy; Erythrocytes; Hemolysis; Heterocyclic Compounds; Hydrogen-Ion Concentration; Iron; Kinetics; Ligands; Magnetic Phenomena; Magnetic Resonance Spectroscopy; Manganese; Mice; Models, Molecular; Quantum Theory; Rats; Semicarbazides; Spectrophotometry, Infrared; Thermodynamics; Thermogravimetry; Thiones