Anti-plasmodial activity of aroylhydrazone and thiosemicarbazone iron chelators: Effect on erythrocyte membrane integrity, parasite development and the intracellular labile iron pool

Abstract

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 μM, respectively) than DFO (IC50 = 23.43 ± 3.40 μM). 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 activity, 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.

ONO‐Pincer‐Type Coumarin‐Based Copper(II) Metalates: Effect on Alzheimer's Disease Pathologies in Caenorhabditis elegans

“…The angle O(4)‐Cu(1)‐O(9) (144.81°) was significantly less compared to 180°, indicating severe distortion from the octahedral geometry. The observed bond distances are related to the reported values [16,22–24] …”

“…Several articles evidence the antimicrobial, DNA cleavage, and anticancer activity of copper complexes containing Schiff bases [9–12] . Coumarins are widely studied naturally occurring compounds, which are well known for their pharmacological and biological responses like antimicrobial, anticoagulant, antitumor, anti‐HIV, chemotherapeutics, and bio‐analytical reagents [13–16] . Certain coumarin derivatives viz .…”

“…[9][10][11][12] Coumarins are widely studied naturally occurring compounds, which are well known for their pharmacological and biological responses like antimicrobial, anticoagulant, antitumor, anti-HIV, chemotherapeutics, and bio-analytical reagents. [13][14][15][16] Certain coumarin derivatives viz. clorobiocin and novobiocin are commercialized as prescription drugs.…”

High Iron Stores in the Low Malaria Season Increase Malaria Risk in the High Transmission Season in a Prospective Cohort of Rural Zambian Children

“…The LIP has been defined as a transitory form of metabolically active, chelatable, nonbound iron (26,30). The LIP hypothesis is supported by several studies showing the inhibitory effects of iron chelators on parasite growth and development (31)(32)(33)(34).…”

An investigation on 3-acetyl-7-methoxy-coumarin Schiff bases and their Ru(ii) metallates with potent antiproliferative activity and enhanced LDH and NO release

“…Thiosemicarbazides are a versatile class of compounds with indispensable properties such as antitumor, antifungal, antibacterial, antiviral, antiparasitic, etc. [1][2][3][4][5][6] They are N, S donor ligands whose activity can be greatly enhanced by the presence of additional donor sites and a variety of coordination modes can be shown by these systems. [7][8][9] Potential ligands are formed by attaching thiosemicarbazides with carbonyl compounds having a heterocyclic moiety.…”