The Single Crystal X‑ray
Structure of β‑Hematin
DMSO Solvate Grown in the Presence of Chloroquine, a β‑Hematin
Growth-Rate Inhibitor
- Publication date
- Publisher
Abstract
Single crystals of solvated β-hematin were grown
from a DMSO
solution containing the antimalarial drug chloroquine, a known inhibitor
of β-hematin formation. In addition, a kinetics study employing
biomimetic lipid–water emulsion conditions was undertaken to
further investigate the effect of chloroquine and quinidine on the
formation of β-hematin. Scanning electron microscopy shows that
the external morphology of the β-hematin DMSO solvate crystals
is almost indistinguishable from that of malaria pigment (hemozoin),
and single crystal X-ray diffraction confirms the presence of μ-propionato
coordination dimers of iron(III) protoporphyrin IX. The free propionic
acid functional groups of adjacent dimers hydrogen bond to included
DMSO molecules, rather than forming carboxylic acid dimers. The observed
exponential kinetics were modeled using the Avrami equation, with
an Avrami constant equal to 1. The decreased rate of β-hematin
formation observed at low concentrations of both drugs could be accounted
for by assuming a mechanism of drug adsorption to sites on the fastest
growing face of β-hematin. This behavior was modeled using the
Langmuir isotherm. Higher concentrations of drug resulted in decreased
final yields of β-hematin, and an irreversible drug-induced
precipitation of iron(III) protoporphyrin IX was postulated to account
for this. The model permits determination of the equilibrium adsorption
constant (<i>K</i><sub>ads</sub>). The values for chloroquine
(log <i>K</i><sub>ads</sub> = 5.55 ± 0.03) and quinidine
(log <i>K</i><sub>ads</sub> = 4.92 ± 0.01) suggest
that the approach may be useful as a relative probe of the mechanism
of action of novel antimalarial compounds