Crystal Nucleation, Growth, and Morphology of the Synthetic Malaria Pigment β-Hematin and the Effect Thereon by Quinoline Additives:  The Malaria Pigment as a Target of Various Antimalarial Drugs SolomonovInna OsipovaMaria FeldmanYishay BaehtzCarsten KjaerKristian RobinsonIan K. WebsterGrant T. McNaughtonDon WoodBayden R. WeissbuchIsabelle LeiserowitzLeslie 2007 The morphology of micrometer-sized β-hematin crystals (synthetic malaria pigment) was determined by TEM images and diffraction, and by grazing incidence synchrotron X-ray diffraction at the air−water interface. The needle-like crystals are bounded by sharp {100} and {010} side faces, and capped by {011} and, to a lesser extent, by {001} end faces, in agreement with hemozoin (malaria pigment) crystals. The β-hematin crystals grown in the presence of 10% chloroquine or quinine took appreciably longer to precipitate and tended to be symmetrically tapered toward both ends of the needle, due to stereoselective additive binding to {001} or {011} ledges. Evidence, but marginal, is presented that additives reduce crystal mosaic domain size along the needle axis, based on X-ray powder diffraction data. Coherent grazing exit X-ray diffraction suggests that the mosaic domains are smaller and less structurally stable than in pure crystals. IR-ATR and Raman spectra indicate molecular based differences due to a modification of surface and bulk propionic acid groups, following additive binding and a molecular rearrangement in the environment of the bulk sites poisoned by occluded quinoline. These results provided incentive to examine computationally whether hemozoin may be a target of antimalarial drugs diethylamino-alkoxyxanthones and artemisinin. A variation in activity of the former as a function of the alkoxy chain length is correlated with computed binding energy to {001} and {011} faces of β-hematin. A model is proposed for artemisinin activity involving hemozoin nucleation inhibition via artemisinin−β-hematin adducts bound to the principal crystal faces. Regarding nucleation of hemozoin inside the digestive vacuole of the malaria parasite, nucleation via the vacuole's membranous surface is proposed, based on a reported hemozoin alignment. As a test, a dibehenoyl-phosphatidylcholine monolayer transferred onto OTS−Si wafer nucleated far more β-hematin crystals, albeit randomly oriented, than a reference OTS−Si.