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Chapter 1: Introduction Investigating Ethnopharmacology-based Natural Product leads for Antimalarial Drug Discovery Maryam Shehu Idris-Usman School of Environment and Life Sciences College of Science and Technology University of Salford, Manchester, UK Submitted in Partial Fulfilment of the Requirements for the Degree of Doctor of Philosophy, September 2016 i DECLARATION I certify that this thesis, which I submit to the University of Salford a partial fulfilment of the requirements for a Degree of Doctor of Philosophy, is a presentation of my own research work. Wherever contributions of others are involved, every effort is made to indicate this clearly with due reference to the literature and acknowledgement of collaborative research and discussions. The content of this thesis has not been submitted for a higher degree at this or any other university. ii TABLE OF CONTENTS DECLARATION………………………………………………………………………………………………………………………………..II LIST OF FIGURES…………………………………………………………………………………………………………………………….XI LIST OF TABLES………………………………………………………………………………………………………………………………XIV ACKNOWLEDGEMENTS………………………………………………………………………………………………………………….XV ABBREVIATIONS…………………………………………………………………………………………………………………………….XVI ABSTRACT……………………………………………………………………………………………………………………………………XVIII CHAPTER…………………………………………………………………………………….1 INTRODUCTION…………………………………………………………………………….1 1.1 History of malaria epidemiology……………………………………………………...1 1.2 Malaria distribution and transmission………………………………………………...3 1.3 Malaria eradication and control……………………………………………………….4 1.4 Discovery of the Plasmodium from a historical perspective………………………….8 1.5 Plasmodium species and life cycle……………………………………………………9 1.5.1 Species and symptoms………………………………………………………...9 1.5.2 Life cycle……………………………………………………………………..10 1.5.3 Erythocytic stages of P. falciparum………………………………………………13 1.6 Clinical symptoms……………………………………………………………………14 1.7 Prevention of malaria……………………………………………………………......15 1.7.1 Vector control……………………………………………………………… 15 1.7.2 Vaccine development………………………………………………………...16 1.7.3 Chemoprophylaxis……………………………………………………………17 1.8 Chemotherapy in malaria……………………………………………………………18 1.8.1 Classification by biological activity………………………………………….18 1.8.2 Classification by structure……………………………………………………20 1.8.2.1 The 4-aminoquinolines………………………………………………….20 1.8.2.2 Arylamino-alcohols……………………………………………………..22 1.8.2.3 The 8-aminoquinolines………………………………………………….22 iii 1.8.2.4 Artemisinins and related compounds…………………………………...23 1.8.3 Antibiotics……………………………………………………………………24 1.8.4 Antifolates……...…………………………………………………………….24 1.8.4.1 Inhibitors of DHFR……………………………………………………...26 1.8.4.2 DHPS inhibitors…………………………………………………………27 1.8.4.3 Pyrimethamine and sulfadrug combinations…………………………………………………………….27 1.8.4.4 Trimethoprim and sulfa-drugs…………………………………………...28 1.8.5 New drugs…………………………………………………………………….28 1.9 Antimalarial drug resistance………………..……………………………………………29 1.9.1 Background to antimalarial resistance………………………………………..30 1.9.2 Mechanisms of resistance…………………………………………………….32 1.9.3 Factors contributing to resistance…………………………………………….33 1.10 Combination therapy…………………………………………………………………35 1.11 Drug discovery process………………………………………………………………36 1.12 Approach to drug discovery………………………………………………………….37 1.12.1 Random screening of compounds……………………………………………38 1.12.2 Rational drug design………………………………………………………….38 1.13 Natural product as a route to drug discovery……………….………………………..39 1.13.1 Historical importance of natural products as antimalarials…..……………....42 1.13.2 Discovery of quinine…………………………………………………………43 1.13.3 Artemisia annua……………………………………………………………………...44 1.13.4 Other natural product derived antimalarials………………………………….45 1.13.5 Classes of natural product compounds……………………………………….45 1.13.6 Natural product drug discovery process for malaria…………………………46 1.13.7 Current techniques in natural product drug discovery……………………….47 1.13.8 Research and development pathways for medicinal plants………………….50 1.13.9 Herbal medicine vs phytopharmaceutical drug……………………………...52 1.14 The concept of reverse pharmacology……………………………………………….53 1.14.1 Case studies in reverse pharmacology/phytopharmaceutical drugs development………………………………………………………………….56 1.14.1.1 India as a case study………………………………………………….56 1.14.1.2 Brazil as a case study………………………………………………..57 1.14.1.3 Africa as a case study………………………………………………...57 iv 1.15 Methods used for natural product discovery for malaria…………………………….59 1.16 Phenotypic screening for malaria……………………………………………………63 1.17 Chapter conclusion……………...…………………………………………………...64 1.18 Project objectives……………………………………………………………………66 CHAPTER 2 ………………………………………………………………………………...66 MATERIALS AND METHODS…………………………………………………………..67 2.1 Establishing P. falciparum cultures and maintenance………………………………67 2.1.1 Complete media………………………………………………………………..67 2.1.2 Blood washing…………………………………………………………………67 2.1.3 Retrieving new cultures from frozen…………………………………………..68 2.1.4 Light microscopy (Giemsa staining)…………………………………………...68 2.1.5 Maintenance of routine P. falciparum cultures…………………………….…..68 2.1.6 Sorbitol synchonization…………………………………………………….….69 2.2 Drug susceptibility assays…………………………………………………………...69 2.2.1 Optimization of the SG-Microplate assay……………………………………....69 2.2.2 Effect of haematocrit level and media on background fluorescence…………....70 2.2.3 Effect of complete media on the SG-Microplate assay……………………….... 70 2.2.4 The adopted optimized SG-Microplate protocol………………………………..71 2.2.5 Optimization of the SYBR-Green assay flow cytometry method (SG-FCM)…..71 2.2.6 Comparison of the Giemsa microscopic test, SG-MicroPlate and SG-FCM……72 2.3 Optimization assay results……………………………………………………………72 2.3.1 Effect of haematocrit and complete on SG-Microplate assay…………………..73 2.3.2 Effect of varying the amount of complete on the SG-Microplate assay………..74 2.3.3 SG-FCM optimization…………………………………………………………..74 2.3.4 Comparing the Giemsa light microscopy, SG-Microplate and SG-FCM assay……………….……………………………………………………………76 2.4 Aqueous and methanolic extraction of the plant material……………………………78 2.5 Drug/extract stock preparation…………………………………………………….....78 2.6 Phytochemical test methods……………………………………………………….....79 2.7 Chapter conclusion…………………………………………………………………...80 CHAPTER 3…………………………………………………………………………………81 ETHNOPHARMACOLOGICAL VALIDATION OF SELECTED PLANTS FROM NIGERIA…………………………………………………..……………………………....81 v 3.1 Introduction…………………………………………………………………………..81 3.2 Validating the ethnopharmacological claims of some plants used for malaria……....81 3.3 Background on selected plants…………………………………………………….…83 3.3.1 Artemisia maciverae……………………………………………………………….…83 3.3.2 Bridelia ferruginea…………………………………………………………………..83 3.3.3 Brysocarpus coccineus………………………………………………………………84 3.3.4 Bombax buonopozense………………………………………………………………85 3.3.5 Boswellia dalzellii……………………………………………………………………87 3.3.6 SN05 coded extrac…t………………………………………………………………..88 3.4 Phase I screening for initial phenotypic antimalarial activity determination………..88 3.4.1 Plant collection and extract preparation……………………………………...88 3.4.2 Antiplasmodial screening of the plant extract……………………………..…88 3.4.2.1 SG-Microplate screen of plant extracts…………………………..…...89 3.4.2.2 Giemsa light microscopy screen for plant extracts……………..…….90 3.4.2.3 FCM Screen for plant extracts………………………………..………91 3.4.2.4 SG-FCM, SG-Microplate and Giemsa assay of chloroquine and dihydroartemisinin as positive controls…………………………………………92 3.5 Phase II Screen of plant extract……………………………………………..………94 3.5.1 Bridelia ferruginea collection……………………………………..………..94 3.5.2 Dose-response analysis of Brysocarpus coccineus using different assays……………………………………………………………………….94 3.5.3 Dose response analysis of aqueous Bridelia ferruginea using different assays…………...…………………………………………………………..96 3.6 Comparing aqueous and methanolic Bridelia ferruginea……………………..……96 3.6.1 Comparing the aqueous and methanolic extract of Bridelia ferruginea using the SG-Microplate assay………………………..…………………...97 3.6.2 Comparing the aqueous and methanolic extract of Bridelia ferruginea using Giemsa light microscopy………………………………….………...98 3.6.3 Comparing the aqueous and methanolic extract of Bridelia ferruginea using FCM assay……………………………………………………….....98 3.7 Time point assay for methanolic Bridelia ferruginea………….……………………….99 3.8 Effect of Bridelia ferruginea on erythocytic stages………..……………………...100 3.8.1 Effect of Bridelia ferruginea on ring stage cultures………………..………101 3.8.2 Effect of Bridelia ferruginea on trophozoite stage cultures…………..……101 vi 3.8.3 Comparing ring and trophozoite stage challenged cultures…………...……101 3.9 Phytochemical chemical screening of Bridelia ferruginea……..……………………..103 3.10 Chapter conclusion……………………………………………..………………….104 CHAPTER 4 …………………………………..…………………………………………..105 INVESTIGATING THE MECHANISM OF ACTION OF METHANOLIC BRIDELIA FERRUGINEA…………….…………………………………………………………..105 4.1 Introduction………………………………………………………………………….105 4.2 Haem detoxification…………………………………………………………...…….106 4.3 Structure of haemozoin………………………………………………………………107 4.4 Haem aggregation……………………………………………………………………108 4.5 Role of haemozoin in malaria pathogenesis………………………………………….108 4.6 Haemozoin as a target for antimalarials………………………………………………108 4.7 In vitro methods used for haemozoin detection and inhibition………………………110 4.8 Method optimization for the inhibition of β-haematin formation for extract screening………………………...…………………………………………………..110 4.8.1 Protocol 1: Optimization assay for β-haematin formation…………………....111 4.8.1.1 Materials……………………………………………………………...111 4.8.1.2 Method……………………………………………………………......111 4.8.1.3 Result…………………………………………………………………111
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