Crystal nucleation, growth, and morphology of the synthetic malaria pigment beta-hematin and the effect thereon by quinoline additives: the malaria pigment as a target of various antimalarial drugs.
The morphology of micrometer-sized beta-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 beta-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 beta-hematin. A model is proposed for artemisinin activity involving hemozoin nucleation inhibition via artemisinin-beta-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 beta-hematin crystals, albeit randomly oriented, than a reference OTS-Si.
Solomonov
Inna
I
Department of Materials and Interfaces, The Weizmann Institute of Science, 76100-Rehovot, Israel.
Osipova
Maria
M
Feldman
Yishay
Y
Baehtz
Carsten
C
Kjaer
Kristian
K
Robinson
Ian K
IK
Webster
Grant T
GT
McNaughton
Don
D
Wood
Bayden R
BR
Weissbuch
Isabelle
I
Leiserowitz
Leslie
L
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000138:chemical synthesis; D001665:Binding Sites; D011232:Chemical Precipitation; D002738:Chloroquine / Q000008:administration & dosage; D019281:Dimerization; D016503:Drug Delivery Systems; D006420:Hemeproteins / Q000187:drug effects*; D046529:Microscopy, Electron, Transmission; D011422:Propionates / Q000737:chemistry; D011804:Quinolines / Q000008:administration & dosage*; D013059:Spectrum Analysis, Raman; D013237:Stereoisomerism; D014961:X-Ray Diffraction
D000962:Antimalarials; D006420:Hemeproteins; D011422:Propionates; D011804:Quinolines; C020753:hemozoin; D002738:Chloroquine; C037219:quinoline; C029658:propionic acid