Alkoxide coordination of iron(iii) protoporphyrin IX by antimalarial quinoline methanols: a key interaction observed in the solid-state and solution

Abstract

The quinoline methanol antimalarial drug mefloquine is a structural analogue of the Cinchona alkaloids, quinine and quinidine. We have elucidated the single crystal X-ray diffraction structure of the complexes formed between racemic erythro mefloquine and ferriprotoporphyrin IX (Fe(iii)PPIX) and show that alkoxide coordination is a key interaction in the solid-state. Mass spectrometry confirms the existence of coordination complexes of quinine, quinidine and mefloquine to Fe(iii)PPIX in acetonitrile. The length of the iron(iii)-O bond in the quinine and quinidine complexes as determined by Extended X-ray Absorption Fine Structure (EXAFS) spectroscopy unequivocally confirms that coordination of the quinoline methanol compounds to Fe(iii)PPIX occurs in non-aqueous aprotic solution via their benzylic alkoxide functional group. UV-visible spectrophotometric titrations of the low-spin bis-pyridyl-Fe(iii)PPIX complex with each of the quinoline methanol compounds results in the displacement of a single pyridine molecule and subsequent formation of a six-coordinate pyridine-Fe(iii)PPIX-drug complex. We propose that formation of the drug-Fe(iii)PPIX coordination complexes is favoured in a non-aqueous environment, such as that found in lipid bodies or membranes in the malaria parasite, and that their existence may contribute to the mechanism of haemozoin inhibition or other toxicity effects that lead ultimately to parasite death. In either case, coordination is a key interaction to be considered in the design of novel antimalarial drug candidates.

Modulation of Antimalarial Activity at a Putative Bisquinoline Receptor In Vivo Using Fluorinated Bisquinolines

“…The crystal structure of both heme [56a] and al imited number of antimalarials of the quinolinem ethanol class covalently bound to heme have been obtained, butt he 4-aminoquinoline class has provede lusive [56b] and investigators have resorted to EXFAS studies and modeling studies. [59] This type of covalent adduct can enforce a p···p interaction between ligand and receptor to minimize intramolecular interactions. [59] This type of covalent adduct can enforce a p···p interaction between ligand and receptor to minimize intramolecular interactions.…”

“…[59] However,a ne quivalent 4-aminoquinoline crystal structure, such as for chloroquine 4a,has yet to be found. In this structure, the mefloquine was protonateda tt he aliphatic (piperidyl) rather than the aromatic nitrogen,w hich is consistent with the calculations above and with crystallographic observations.…”

“…[3b, c, 5b, c, 20, 21, 23, 29, 56, 60, 61, 63-65] For bis-trifluoromethylquinolines, the p···p type interaction was less stable than the corresponding hydrogen bonded mode,w hich favors interaction at the secondary amine rather than the sterically encumbered nitrogen buttressed between the trifluoromethyl groups (see Figure 7a nd the Supporting Information, S33). [59] Not only do the substituents affect the electronic properties of the molecule, they also offer alternative, preferential hydrogen-bonding sites, and their stericb ulk will reduce the possibility of interactions from the adjacent endocyclic nitrogena tom. [23] Conclusion These resultss how that the inclusiono fC F 3 substituentsh as am ajor impact on the geometry of drug interaction with the antimalarial heme receptor.T his maye xplain why the substituent pattern presenti n1a is optimized for antimalarial activity only in the quinoline methanolc lass and this induces axial attack onto the porphyrin as verified recently by crystal structures.…”

“…[21] Consequently,i thas been shown that the mode of action of quinoline methanols is at heme but, unlike 4-aminoquinolines, they displace the axial group to form aF e ÀOb ond, which is also found in all other compounds of this class (e.g.,h alofantrine, [57] Cinchona alkaloids especially 3 [58] and 1a). [59] This type of covalent adduct can enforce a p···p interaction between ligand and receptor to minimize intramolecular interactions.…”

“…Thishydrogen atom formed av ery strongh ydrogen bond to the heme hydroxide with NÀ H···O 1.58 .O ther hydrogen bonds involved two carboxylic oxygen atoms OÀH···O 2.07 and an OÀH···F between the ligand and heme of 2.45 .T he energy of interaction was À40.2 kcal mol À1 .T herefore, it could be considered to pre-organize this fluorinated quinolone methanolt oattack heme by forming an axial FeÀO(alkoxide) bond as seen in crystal structures. [59] However,a ne quivalent 4-aminoquinoline crystal structure, such as for chloroquine 4a,has yet to be found. [61] Clearly,t he interaction of ligands with heme does not occur in the gasp hase; therefore, the calculations were repeated by using the solventw ater PCM method in Gaussian09.…”