Metalloantimalarials:  Targeting of P. falciparum Strains with Novel Iron(III) and Gallium(III) Complexes of an Amine Phenol Ligand

Abstract

Emergence of chloroquine (CQ)-resistant Plasmodium falciparum strains necessitates discovery of potent and inexpensive antimalarial drugs. The high cost of new drugs negatively impacts their access and distribution in the regions of the world with scarce economic resources. While exploring structure-activity relationships, using gallium(III) as a surrogate marker for iron(III), we found cationic, and moderately hydrophobic, compounds, [[1,12-bis(2-hydroxy-3-ethyl-benzyl)-1,5,8,12-tetraazadodecane]metal(III)](+) (metal = Fe(III) and Ga(III); [Fe-3-Eadd](+), 3; [Ga-3-Eadd](+), 4), that possessed antimalarial activity. Crystal structure analyses revealed octahedral geometry for these complexes. The RP-HPLC analysis, after incubation in PBS or HEPES buffer (pH 7.4) at 37 degrees C for 3 days, detected only parental compounds thereby providing evidence for stability under physiological conditions. Both 3 and 4 demonstrated promising half-maximum inhibitory concentration (IC(50)) values of approximately 80 and 86 nM in the CQ-sensitive HB-3 line, respectively. However, both 3 and 4 were found to possess elevated IC(50) values of 2.5 and 0.8 microM, respectively, in the CQ-resistant Dd2 line, thus displaying preferential cytotoxicity toward the CQ-sensitive HB3 line. In cultured parasites, 3 and 4 targeted hemozoin formation. Thus, these compounds acted similarly to chloroquine with regard to action and resistance, despite the lack of structural similarity to quinolines. Finally, similarity in coordination chemistry, stability, and antimalarial cytotoxicity profiles indicated that gallium(III) ion can serve as a template for iron(III) in structure elucidation of active molecules in solution.

Synthesis, characterization and DFT study of new water-soluble aluminum(III), gallium(III) and indium(III) Schiff base complexes: effect of metal on the binding propensity with bovine serum albumin in water

“…Thus, aluminum and its complexes (such as Schiff base complexes) and their biological activity attract some attentions [9]. Other group 13 Schiff base complexes [gallium(III) and indium(III)] [10] are proven to have antimalaria properties [11][12][13], however, Ga(III) Schiff base complexes were previously reported as potential positron emitting Abstract In this work, three new water-soluble aluminum(III), gallium(III) and indium(III) Schiff base complexes; [M(L) NO 3 ], where L denotes; N,N′-bis(5-sulfosalicyliden)-1,2-phenylendiamin (5-SO 3 -1,2-salophen); were synthesized and characterized by UV-Vis spectroscopy, 1 H NMR, FT-IR, thermal gravimetry and C.H.N analyses. Also, the optimized structure and the energy level of the frontier orbitals for the complexes were computed using B3LYP/LANL2DZ method and 6-311g basis set.…”

Therapeutic Drugs for Targeting Chloroquine Resistance in Malaria

“…However, both 50 and 51 have been found to possess elevated IC 50 values of 2.5 µM and 0.8 µM, respectively, in the CQ-resistant Dd2 line (Fig. 4), thus displaying preferential activity towards the CQ-sensitive HB3 line [103]. Both 50 and 51 targeted hemozoin formation in cultured parasites [103].…”

“…Schiff-base phenolate-or amine phenol-metal complexes comprise another class of coordination compounds that possess favorable balance of hydrophobicity and delocalized cationic charge for enhanced cell membrane permeability [97]. Obtained from commercially available inexpensive precursors, these Recently, while exploring structure-activity relationships by using gallium(III) as a surrogate metal for iron(III), we have found cationic, and moderately hydrophobic metallodrugs, [Fe-3-Eadd] + 50 and [Ga-3-Eadd] + 51 that possessed antimalarial activity [103]. Those compounds, which contain metals in octahedral environment, have been found to be stable under physiological conditions.…”

“…Both 50 and 51 targeted hemozoin formation in cultured parasites [103]. Thus, these compounds acted similar to chloroquine with regard to action and resistance, despite the lack of structural similarity to chloroquine [103].…”

Cytotoxic gallium complexes containing thiosemicarbazones derived from 9-anthraldehyde: Molecular docking with biomolecules

“…Among these metals, platinum and ruthenium are probably the most well-known. However, gallium is considered to be the second metal, (after platinum), to have generated much research interest [1], with detailed investigations occurring from the 1970s [2 - 7]. The attractiveness of gallium as a therapeutic agent stems primarily from its biological and chemical mimicry of iron.…”