Thesis (PhD)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: The work in this dissertation provides structural and kinetic insight into the mechanism of
action of quinoline antimalarial drugs which may aid rational drug design. Quinoline
antimalarial drug-ferrihaem (Fe(III)PPIX) complexes were investigated. Single crystal Xray
diffraction (SCD) structures of the complexes formed between Fe(III)PPIX and the
quinoline methanol antimalarials quinine, quinidine and mefloquine have been determined,
and are the first observed structures of complexes formed between free Fe(III)PPIX and
quinoline antimalarial compounds. Quinine, quinidine and mefloquine are shown to have a
three-point binding mode to Fe(III)PPIX, which comprises direct coordination of the drug
to the Fe(III) centre through its benzylic alcohol functionality, π-stacking between the drug
and porphyrin aromatic systems, and intramolecular hydrogen bond formation between the
porphyrin propionate group and the protonated quinuclidine nitrogen atom of the drug in
the case of quinine and quinidine, and formation of an intramolecular hydrogen bonding
network in the case of mefloquine. Extended X-ray absorption fine structure spectroscopy
(EXAFS) was use to elucidate structural information of Fe(III)PPIX-drug complexes in
solution, and indicates that coordination persists in solution.
The protocol for lipid-mediated formation of β-haematin, where monopalmitic glycerol
was used as a model lipid, was successfully modified to incorporate antimalarial drugs into
the aqueous layer in order to investigate drug activity under biologically-relevant
conditions. Four compounds were chosen, namely chloroquine and amodiaquine, both 4-
aminoquinolines and quinine and quinidine. IC50 values for the inhibition of β-haematin
formation show good correlation with biological activities determined against a
chloroquine-sensitive Plasmodium falciparum strain. The lipid-water interface system was
further used to investigate the effects of quinine, quinidine chloroquine and amodiaquine
on the kinetics of β-haematin formation. The results led to the development of a kinetic
model based on the Avrami equation and the Langmuir isotherm. The data strongly support
a mechanism of antimalarial drug action by adsorption to the growing face of haemozoin,
with precipitation of Fe(III)PPIX at high drug concentrations accounting for decreased
yields. Adsorptions constants (log Kads) determined for each drug show a strong correlation
with biological activity. Finally, the first SCD structure of the μ-propionato dimer of
Fe(III)PPIX, the structural unit of haemozoin, has been determined as its DMSO solvate.
EXAFS suggests that this species is only formed upon nucleation, with the π-π dimer
species being favoured in solution. / AFRIKAANSE OPSOMMING: Die werk in die dissertasie verleen struktuur en kinetiese insig in the meganisme van
aktiwiteit vir kinolien antimalariamiddels wat kan bydra tot die ontwikkeling van nuwe
medisyne. Kinolien antimalariamiddel-ferriheem (Fe(III)PPIX) komplekse was ondersoek.
Navorsing is gedoen op die enkelkristal X-straaldiffraksie strukture van die komplekse
gevorm tussen Fe(III)PPIX en die kinolien metanol antimalaria middels kinien, kinidien en
mefloquine. Die strukture is die eerste komplekse wat waargeneem is tussen vrye
Fe(III)PPIX en kinolien antimalariamiddels. Kinien, kinidien en mefloquine het ʼn driepunt
bindingsvorm, direkte koördinasie met die Fe(III) deur die bensielalkohol groep, ʼn π-
stapel tussen die middel en die porfirien aromatiese sisteem, ʼn intramolekulêre
waterstofbinding tussen the porfirienpropionaat funksie en die geprotoneerde kinuklidien
stikstofatoom (kinien en kinidien) en ʼn netwerk van intramolekulêre waterstof bindings
(mefloquine) insluit. Uitgebreide X-straal absorpsie fyn struktuur spektroskopie (EXAFS)
is gebruik om inligting oor Fe(III)PPIX-middel komplekse in oplossing te verkry en het
aangedui dat die koördinasie in oplossing voorkom.
Deur gebruik te maak van monopalmitiengliserol as die lipid in the lipid-water interfase
sisteem, waar antimalariamiddels suksesvol in die buffer geïnkorporeer was, was die
middel se aktiwiteit onder biologiese kondisies geondersoek. Vier middels was gekies
naamlik, chloroquine en amodiaquine, albei 4-aminokinoliene en kinien en kinidien om die
IC50-waarde vir inhibisie van β-hematien vorming te bepaal. Die IC50 waardes het ʼn goeie
korrelasie met biologiese aktiwiteite teen die chloroquine-sensitiewe Plasmodium
falciparum stam gewys. Die lipid-water interfase-sisteem was ook gebruik om die effek
van kinien, kinidien, chloroquine en amodiaquine op die kineties effek op die vorming van
β-hematien te ondersoek. Die resultate het gelei to die ontwikkeling van die kinetiese
model gebaseer op die Avrami vergelyking en die Langmuir isoterm. Die data ondersteun
ʼn meganisme van middel aksie waar die middel teen die groeiende vlak van hemosoïen
kristal adsorbeer. Die neerslag van Fe(III)PPIX wat vorm by hoë konsentrasies, het gelei
tot laer opbrengste. Die adsorpsiekonstante (log Kads) bepaal vir elke middel, het goeie
korrelasie met biologiese aktiwiteit getoon. Enkelkristal X-straaldiffraksie strukture van μ-
propionatodimeer van Fe(III)PPIX, die struktuur eenheid van hemosoïen, was bepaal as ʼn
DMSO solvaat. EXAFS het aangedui dat die spesie slegs by kernvorming ontstaan en dat
die π-π dimeerspesie in oplossing voorkom.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/85621 |
| Date | 12 1900 |
| Creators | Gildenhuys, Johandie |
| Contributors | De Villiers-Chen, Katherine, Le Roex, Tanya, Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
| Format | xiii, 246 p. : col. ill. |
| Rights | Stellenbosch University |
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