Linear free energy relationships predict coordination and π-stacking interactions of small molecules with ferriprotoporphyrin IX

In order to better understand the interaction of antimalarial compounds with ferriprotoporphyrin IX (Fe(III)PPIX), association constants of pyridines, imidazoles, amines and phenolates with Fe(III)PPIX and protoporphyrin IX (PPIX) have been measured spectrophotometrically in 40% (v/v) aq. DMSO at pH 7.4. The pH independent log association constants for coordination of nitrogen donor ligands exhibit a linear free energy relationship (LFER) with the pKa of the donor atom. Association through π-stacking interactions (log Kπ) with PPIX and Fe(III)PPIX increases with the number of π-electrons in the aromatic ring system. These findings indicate that in the aqueous milieu of the malaria parasite digestive vacuole, coordination to the Fe(III) center of the porphyrin is necessarily very weak, while π-stacking interactions will be much stronger. On the other hand, in environments in which proton competition is absent, coordination will dominate, with the most basic donor atoms forming the strongest complexes with Fe(III)PPIX. The lipid nanospheres within the digestive vacuole which are now known to be the location of conversion of Fe(III)PPIX to hemozoin could possibly be such an environment, making both types of interaction relevant to the design of new hemozoin inhibitors.

Graphical AbstractAssociation constants are proportional to pKa for coordination, and to number of aromatic π-electrons for π-stacking with free ferriprotoporphyrin IX.Figure optionsDownload full-size imageDownload as PowerPoint slide