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1.2 Anti-Malarial Drugs

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1.2 Anti-Malarial Drugs Dissertation Submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-Carola University of Heidelberg, Germany for the degree of Doctor of Natural Sciences Presented by Yulin Wang born in Fuxin, China Oral examination:………………… Parasitological Evaluation of SC81458 and SC83288, a Novel Class of Drugs against Plasmodium Falciparum Referees : Prof. Dr. Michael Lanzer Prof. Dr. Luise Krauth-Siegel Ich erkläre hiermit, dass ich die vorgelegte Dissertation selbst verfasst und mich dabei keiner anderen als der von mir ausdrücklich bezeichneten Quellen und Hilfen bedient habe. Ich erkläre hiermit, dass ich an keiner anderen Stelle ein Prüfungsverfahren beantragt bzw. die Dissertation in dieser oder anderer Form bereits anderweitig als Prüfungsarbeit verwendet oder einer anderen Fakultät als Dissertation vorgelegt habe. Die vorgelegte Arbeit wurde am Hygieneinstitut, Abteilung Parasitlogie der Universität Heidelberg in der Zeit März 2006 bis Oktober 2009 unter der Leitung von Prof. Dr. Michael Lanzer durchgeführt. Acknowledgements Acknowledgements First of all, I would like to thank Prof. Dr. Lanzer, for giving me the opportunity to join his lab and for his constant trust and support throughout the course of my PhD. I would also like to thank Prof. Stein, for his excellent guidance on drug resistance research. Furthermore, I am very thankful to Dr. Stefano, my nice cooperator from 4SC, for his excellent contributions to our project. I would like to thank all the members past and present of the Lanzer lab for their consistently good help. Finally, I would like to thank my family for their love and support throughout this time. I Abbreviations ABBREVIATIONS 3D 3 Dimensional ACT Artemisinin-based combination therapy ADMET absorption, distribution, metabolism, excretion and toxicity AG Aktiengesellschaft ATP Adenosine triphosphate cm centimeter CQR Chloroquine resistance CRT Chloroquine resistance transporter DHFR Dihydrofolate reductase DHPS Dihydropteroate synthase DMSO Dimethylsulfoxide DNA Desoxyribonucleic acid E Glutamic acid Fig. Figure GmbH Gesellschaft mit beschränkter Haftung hrs hour H2O Water IC50 half maximal inhibitory concentration IC90 90% of maximal inhibitory concentration IC99 99% of maximal inhibitory concentration L Leucine m Milli M Molar or Methionine m Meter MDR Multi-drug resistance min Minute MMV Medicines for Malaria Venture n Nano ND Not determined NMR Nuclear magnetic resonance NPP New Permeation Pathway O2 Oxygen II Abbreviations oC Celcium degrees P. Plasmodium PCT Parasite clearance time Pf Plasmodium falciparum pH Potential hydrogenii PK Pharmacokinetics PMR Parasite multiplication rate PPM Parasite Plasma Membrane PV Parasitophorous Vacuole PVM Parasitophorous Vacuolar Membrane QSAR Quantitative structure-activity relationship RPMI Rosewell Park Memorial Institute RT Room Temperature or Reverse Transcriptase SAR Structure-activity relationship SBDD Structure based drug design sec Second SERCA Sarco/Endoplasmic Reticulum Ca2+-ATPase v/v volume to volume vol Volume w/w weight to volume WHO World Health Organization X-ray Roentgen ray μ Micro III Table of contents TABLE OF CONTENTS Acknowledgements……………………………………………………………………………Ⅰ Abbreviations………………………………………………………………………………….Ⅱ Table of contents………………………………………………………………………………Ⅳ Summary………………………………………………………………………………………...1 Zusammenfassung……………………………………………………………………………….2 1 Introduction……………………………………………………………………………...…3 1.1 Malaria…………………………………………………………………………………3 1.1.1 Life cycle…………………………………………………………………………..4 1.1.2 Clinical manifestations…………………………………………………………….6 1.2 Anti-malarial drugs…………………….………………………………………………7 1.2.1 Anti-malarial drugs in clinical use…………………...……………………………7 1.2.1.1 Arylaminoalcohols………….…………………………………………………7 1.2.1.1.1 Quinine……………………………………………………………………7 1.2.1.1.2 Mefloquine……………………...…………………………………………8 1.2.1.1.3 Halofantrine………………….……………………………………………8 1.2.1.1.4 Lumefantrine…………………...…………………………………………9 1.2.1.2. Aminoquinolines……………….………….…………………………………9 1.2.1.2.1 Chloroquine……………………………….………………………………9 1.2.1.2.2 Amodiaquine………………………………………………………………10 1.2.1.3 8-Aminoquinolines…………………………………………..………………11 1.2.1.3.1 Primaquine………………………………………………….……………11 1.2.1.4 Artemisinines…………………………………...……………………………12 1.2.1.5 Antifolates……………………………………………………………………13 1.2.1.5.1 Chloroguanide (Proguanil)………………………………………………13 1.2.1.5.2 Dapsone……………………………………………………...…………..13 1.2.1.5.3 Pyrimethamine and Sulphadoxine……………………………………….13 1.2.1.6 Antibiotics……………………………………………………………………14 1.2.1.6.1 Tetracyclines……………………………………………………......……14 1.2.1.7 Inhibitors of the respiratory chain…………………………………...……….14 1.2.1.7.1 Atovaquone…………………………………………………………...….14 IV Table of contents 1.2.2 Anti-malarial drugs combination in clinical use…………………………………15 1.2.2.1 Artemisinin-based combination therapies (ACTs)…………………………..15 1.2.2.1.1 Artemether-Lumefantrine (CoartemTM)……………………………..…16 1.2.2.1.2 Artesunate-mefloquine…………………………………………………..16 1.2.2.1.3 Artesunate-Amodiaquine…………………………………………….…..16 1.2.2.1.4 Dihydroartemisinin–piperaquine (Artekin™)……………………...……16 1.2.2.2 Atovaquone-Proguanil (MalaroneTM)………………………………………17 1.2.2.3 Pyrimethamine-Sulphadoxine (FansidarTM)………….…………………….17 1.2.3 Drugs in clinical studies for future chemotherapy……………………………….19 1.2.3.1 Tafenoquine…………………………………………………………….……19 1.2.3.2 AQ-13………………………………………………………………………..19 1.2.3.3 Ferroquine…………………………………………………………...……….19 1.2.3.4 T3………………………………………………………………...…………..19 1.2.3.5 Fosmidomycin………………………………………………………………..20 1.2.3.6 Isoquine…………………………………………………………..…………..20 1.2.4 Anti-malarial drugs combination in clinical studies……………………………..20 1.2.4.1 Chlorproguanil-dapsone-artesunate (Lapdap™)………………………….….20 1.2.4.2 Fosmidomycin-clindamycin……………………………………………...….21 1.2.4.3 Pyronaridine-artesunate (PANDA)…………………………………….…….21 1.3 The reason for the widespread of malaria………………………………………..…..21 1.3.1 No effective vaccine available against malaria…………………………………..21 1.3.2 Drug resistance………………………………………………………………...…22 1.3.2.1Parasite originated drug resistance elements: transporter and enzyme…………..23 1.3.2.1.1 Drug resistance related Plasmodium transporter…………………...……23 1.3.2.1.1.1 PfCRT………………………………………………………………..23 1.3.2.1.1.2 PfMDR1……………………………………………………………..24 1.3.2.1.1.3 Plasmodium falciparum CG2………………………………………..24 1.3.2.1.2 Drug resistance related enzymes………………………………………...24 1.3.2.1.2.1 Plasmodium falciparum dihydrofolate reductase (PfDHFR)………..24 1.3.2.1.2.2 Plasmodium falciparum dihydropteroate synthase (PfDHPS)………25 1.3.2.1.2.3 Plasmodium falciparum ATP6(PfATP6)……………………………25 1.3.2.2 Drug originated drug resistance elements……………………………………26 1.3.2.2.1 In vivo elimination half-life……………………………………………...26 1.3.2.2.2 The gene stability of drug target…………………………………………27 V Table of contents 1.4 The targets used for the development of novel anti-malarial drugs………………….27 1.4.1 The drug targets of Plasmodium Falciparum in biochemical pathways…………27 1.4.1.1 The Plasmodium Falciparum specific biochemical pathways in the apicoplast…..27 1.4.1.2 The Plasmodium Falciparum specific metabolic pathways in the mitochondrial ..28 1.4.1.3 Choline biosynthesis pathway………………………………………………..29 1.4.1.4 Plasmodium Falciparum special proteases…………………………………..29 1.4.1.5 Plasmodium Falciparum Carbonic Anhydrase (CA) inhibitors……………..30 1.4.1.6 Targeting the shikimate pathway…………………………………………….30 1.4.1.7 Microtubule inhibitors……………………………………………………….30 1.4.1.8 Targeting the redox system…………..………………………………………30 1.4.1.9 Targeting the methionine cycle, methylation, and polyamines……………...31 1.4.1.10 Targeting nucleic acid metabolism…………………………………………31 1.4.1.11 Targeting folate metabolism………………………………………………..32 1.4.1.12 Targeting Hematin or the Hemozoin Crystal……………………………….32 1.4.1.13 Targeting Hematin or the Hemozoin Crystal……………………………….33 1.4.2 Other drug targets of Plasmodium Falciparum………………………………..…33 1.4.2.1 New permeability pathways (NPPs)…………………………………………33 1.4.2.2 Parasite transporters………………………………………………………….34 1.5 Aim of this study…………………..…………………………………………………34 2 Material and method……………………………………………………………………...35 2.1 Materials……………………………………………………………………………...35 2.1.1 Equipment………………………………………………………………………..35 2.1.2 Disposables……………………………………………………………………….36 2.1.3 Buffers, media and solutions……………………………………………………..37 2.1.4 Chemicals………………………………………………………………………...37 2.1.5 Plasmodium falciparum strains………………….……………………………….38 2.2 Method………………………………………………….…………………………….38 2.2.1 Cell culture……………………………………………………………………….38 2.2.1.1 In vitro culture of Plasmodium falciparum…………………………………..38 2.2.1.2 Preparation of human serum and erythrocytes……………………………….38 2.2.1.3 Staining of P. falciparum with Giemsa………………………………………39 2.2.1.4 Determining parasitaemia……………………………………………………39 2.2.1.5 Parasite synchronization at Ring stage with sorbitol………………………...39 2.2.1.6 Freezing parasites…………………………………………………………….39 VI Table of contents 2.2.1.7 Thawing parasites……………………………………………………………40 2.2.2 Compound screen………………………………………………….……………..40 2.2.2.1 Compound preparation for screening………………………………………..40 2.2.2.2 [3H]-hypoxanthine incorporation inhibition based anti-malarial compounds screening ..40 2.2.3 Parasitological evaluation of SC81458…………………………………………..42 2.2.3.1 In vitro antiplasmodial assay………………………………………………...42 2.2.3.2 Stage-specific susceptibility………………………………………………….42 2.2.3.3 Time course of Plasmodium falciparum growth inhibition………………….43 2.2.3.4 Drug resistance induce property to Dd2……………………………………..43 3 Results…………………………………………………………………………………….44 3.1 Cell based compounds
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