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INTERACTION OF QUINOLINES AND ARTEMISININ
BASED
ANTIMALARIAL DRUGS WITH FERRIPROTOPORPHYRIN
IX
Mavakala kiazolua Bienvenu
Abstract
Malaria is a major health problem in many countries and
according to an estimate of the WHO, more than 500 million infections occur per
year. Actually, all over the world, malaria is killing one people after 30
seconds. Because of multidrug resistance of Plasmodium falciparum to current
quinoline based drugs, antimalarial drugs are investigated to understand their
mode of action and to provide a ratioanal basis to design new drugs.
Artemisinin, a sesquiterpene obtained from Chinese herbal drug «qinghaosu
«has received considerable as a promising and potent antimalarial in terms
of efficacy and cost.
It has been established that hemin is primarily involved in
the antimalarial activity of antimalarias. Thus, the interaction of these drugs
with hemin may represent a crucial screening test to define their efficacy. In
this study, the interaction of hemin with chloroquine, quinine and quinidine in
50% water-propylene glycol at pH 9, 8.1, 7.4, and 6.8 using using a
spectrophotometric method. In addition, the results indicated that hemin
complexed more strongly with quinidine than with chloroquine and quinine and
the binding constants were pH-dependent. Moreover, it was proved that the
water-propylene glycol mixture is well suitable to the study of the systems
containing hemin and quinoline-based drugs.
Artemisinin and derivates were investigated by UV-Visible
at pH 9 and 7.4 and by HPLC/DAD/MS analysis for their reactivity with hemin. It
has been showed that artesunate and dihydroartemisinin interacted more strongly
with Fe (III) PPIX that artemisinin did. Aqueous DMSO solution is well suitable
studying hemin-artemisnin interaction. Both quinoline and artemisinin drugs-
hemin complexes exhibited 1:1 stoechiometry.
The reported results showed too that hemin and endoperoxide
lactone derived antimalarials slowly react to give rise to several
stereoisomers supramolecular adducts (three for artesunate, seven for
artemisinin and eight isomers for dihydroartemisinin) while in contrast, it has
been reported that only heme (FeII) did react with artesiminin based
drugs.
CONTENTS
CHAPTER 1 INTRODUCTION
CHAPTER 2 LITERATURE SURVEY
2.1 Biology of the malaria parasite
2.1.1 Life cycle of malaria parasite
2.1.2 Hemozoin formation by malaria
parasite
2.2 Some proposed mechanisms of action of
antimalarials drugs
2.2. 1 Mechanism of action of chloroquine
and related antimalarials
2.2 1.1 Extravacuolar mechanisms
2.2.1.2 Intravacuolar mechanisms:
2.2.2 Mechanism of action of artemisinin
and its derivatives
2.3 Mechanism of resistance of parasite to current
drugs
2.4 New strategy in the war against malaria
2.4.1 Discovering Antimalarials: New drug
targets
2.4.2 New generation of antimalarial
drugs: trioxaquines
2.4.3 Vaccine
2.4.4 Genetic approaches
CHAPTER 3 EXPERIMENTAL MATERIALS AND
METHODS
3.1 Materials
3.1.1Property of Chemicals
3.1.2 Apparatus
3.1.3 Physical chemical properties of used solvents
3.2 Preparation of solutions
3.2.1 Test of solubility of drugs and hemin in some usual
solvents
3.2.2 Buffer solutions
3.2.3 Water- DMSO mixture
3.2.4 Water-propylene glycol mixture
3.2.5 Hemin solutions
3.2.6 Quinolines solutions
3.2.7 Artemisinin solutions
3.3 Methods
3.3.1
Ultraviolet/visible molecular spectroscopy
3.3.1.1. General principle
3.3.1.2
Procedural details of hemin-drugs spectrophotometry titrations.
3.3.2 Chromatography method
3.3.2.1 General description of
chromatography
3.3.2.2 Introduction to HPLC/MS
technique
3.3.2.3 HPLC/MS experiments of
hemin-artemisinin compounds interaction
3.4 Data analysis
CHAPTER 4 RESULTS AND
DISCUSSION
4. 1 Choice of the medium
4. 2 Choice of buffers
4.3 Binding reaction of hemin with chloroquine,
quinine and quinidine in water-propylene glycol mixture
4.4 Binding reaction of hemin with artemisinin
compounds
4.4.1 Binding reaction of hemin with
artemisinin, artesunate and dihydroartemisinin in water-DMSO mixture
4.4.2 Binding reaction of hemin with
artesunate in water-propylene glycol mixture
4.4.2 HPLC/MS analysis of hemin-artemisinin based drugs
interaction
CHAPTER 5 CONCLUSIONS
Acknowledgements
References
Appendixes
Publications
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