title: Effects of solvent composition and ionic strength on the interaction of quinoline antimalarials with ferriprotoporphyrin IX.
abstract: Enthalpy-entropy compensation in the interaction of quinoline antimalarials with ferriprotoporphyrin IX (Fe(III)PPIX) in 40% aqueous dimethyl sulfoxide (DMSO) has been compared with that in pure aqueous solution. The data indicate that the degree of desolvation and loss of conformational freedom is virtually identical in both systems. Taken together with previous findings showing that the molar free energies of association of these drugs with Fe(III)PPIX in both solvent systems are very similar, this suggests that the recognition site on the metalloporphyrin is comparable in both cases. This is despite the fact that Fe(III)PPIX exists as a dimer in aqueous solution, but is monomeric in 40% DMSO. Free energies of association of chloroquine, quinine and quinidine with Fe(III)PPIX are largely insensitive to the concentration of sodium perchlorate in 40% DMSO. This demonstrates that electrostatic interactions play only a minor role in the overall stability of these complexes under these conditions. Increasing DMSO concentration greatly weakens the interactions of chloroquine, amodiaquine, quinine, quinidine and 9-epiquinine with Fe(III)PPIX. This suggests that hydrophobic interaction plays a major role in the stability of these complexes. Further investigation of chloroquine has revealed that the free energy of association with Fe(III)PPIX also weakens as a function of decreasing solvent polarity in pure organic solvents. However, the free energies of association are weaker in the mixed aqueous solvent than in pure organic solvents. This indicates that dispersion and electrostatic interactions are relatively strong in the non-aqueous environment. The results demonstrate that any successful model of antimalarial drug-Fe(III)PPIX interactions will need to take both solvation and electrostatic factors into account.
authors.affiliation: Department of Chemistry, University of Cape Town, Private Bag, Rondebosch 7701, South Africa. tegan@science.uct.ac.za
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Egan
authors.forename: Kanyile K
authors.initials: KK
authors.lastname: Ncokazi
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D000431:Ethanol / Q000737:chemistry; D006427:Hemin / Q000737:chemistry* / Q000378:metabolism; D009994:Osmolar Concentration; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D012997:Solvents / Q000737:chemistry*; D013053:Spectrophotometry; D055672:Static Electricity; D013552:Swine; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D000962:Antimalarials; D011804:Quinolines; D012997:Solvents; D014867:Water; D000431:Ethanol; D006427:Hemin; D004121:Dimethyl Sulfoxide