TY - JOUR
T1 - Anti-plasmodial activity of aroylhydrazone and thiosemicarbazone iron chelators
T2 - Effect on erythrocyte membrane integrity, parasite development and the intracellular labile iron pool
AU - Walcourt, Asikiya
AU - Kurantsin-Mills, Joseph
AU - Kwagyan, John
AU - Adenuga, Babafemi B.
AU - Kalinowski, Danuta S.
AU - Lovejoy, David B.
AU - Lane, Darius J. R.
AU - Richardson, Des R.
PY - 2013/12
Y1 - 2013/12
N2 - 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 +/- 2.00 mu M, respectively) than DFO (IC50 = 23.43 +/- 3.40 mu M). 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. (C) 2013 Elsevier Inc. All rights reserved.
AB - 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 +/- 2.00 mu M, respectively) than DFO (IC50 = 23.43 +/- 3.40 mu M). 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. (C) 2013 Elsevier Inc. All rights reserved.
KW - Aroylhydrazone
KW - Thiosemicarbazone
KW - Iron chelator
KW - Plasmodium falciparum
KW - Erythrocytes
KW - PYRIDOXAL ISONICOTINOYL HYDRAZONE
KW - RED-BLOOD-CELLS
KW - MALARIA PARASITE
KW - IN-VITRO
KW - ANTIPROLIFERATIVE ACTIVITY
KW - CHLOROQUINE-RESISTANT
KW - FALCIPARUM MALARIA
KW - OVERLOAD DISEASE
KW - IRON(III)
KW - ANALOGS
U2 - 10.1016/j.jinorgbio.2013.08.007
DO - 10.1016/j.jinorgbio.2013.08.007
M3 - Article
C2 - 24028863
VL - 129
SP - 43
EP - 51
JO - Journal of Inorganic Biochemistry
JF - Journal of Inorganic Biochemistry
SN - 0162-0134
ER -