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 Inna Solomonov Maria Osipova Yishay Feldman Carsten Baehtz Kristian Kjaer Ian K. Robinson Grant T. Webster Don McNaughton Bayden R. Wood Isabelle Weissbuch Leslie Leiserowitz 10.1021/ja0674183.s001 https://acs.figshare.com/articles/journal_contribution/Crystal_Nucleation_Growth_and_Morphology_of_the_Synthetic_Malaria_Pigment_Hematin_and_the_Effect_Thereon_by_Quinoline_Additives_The_Malaria_Pigment_as_a_Target_of_Various_Antimalarial_Drugs/3020101 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. 2007-03-07 00:00:00 hematin hemozoin nucleation inhibition malaria pigment Various Antimalarial DrugsThe morphology bulk propionic acid groups TEM alkoxy chain length crystal mosaic domain size stereoselective additive binding OTS diffraction