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Synthesis and Evaluation of Chromone Derivatives As Inhibitors of Monoamine Oxidase

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Synthesis and Evaluation of Chromone Derivatives As Inhibitors of Monoamine Oxidase Synthesis and evaluation of chromone derivatives as inhibitors of monoamine oxidase AN Mpitimpiti 21253005 Dissertation submitted in fulfilment of the requirements for the degree Magister Scientiae in Pharmaceutical Chemistry at the Potchefstroom Campus of the North-West University Supervisor: Dr ACU Lourens Co-supervisors: Dr A Petzer Prof JP Petzer November 2014 The financial assistance of the National Research Foundation (NRF) and the Medical Research Council (MRC) towards this research is hereby acknowledged. Opinions expressed and conclusions arrived at are those of the author and are not necessarily to be attributed to the NRF or MRC. Acknowledgements • All glory be to God. • I am deeply indebted to the following for their immense support and contribution: o My supervisor - Dr A.C.U Lourens (your guidance is truly boundless). o My co-supervisors, Prof J.P Petzer and Dr A. Petzer. o Dr J.Jordaan. • My mother, Magret Chigeza (for your unconditional love and support). • My family and friends. • All those who knowingly and unknowingly supported me through out this journey. Psalm 115 verse 1: ‘Not to us, O Lord, not to us, but to Your Name be the glory, because of Your love and faithfulness’ i Table of Contents Abstract ...........................................................................................................................iv Opsomming ....................................................................................................................vii List of abbreviations .......................................................................................................xi CHAPTER 1 ..................................................................................................................... 1 INTRODUCTION .............................................................................................................. 1 1.1 BACKGROUND ........................................................................................................... 1 1.1.1 Parkinson’s disease .......................................................................................... 1 1.1.2 Monoamine oxidase .......................................................................................... 2 1.1.3 Chromones as MAO inhibitors .......................................................................... 4 1.2 HYPOTHESIS OF THIS STUDY ...................................................................................... 7 1.3 AIMS AND OBJECTIVES ............................................................................................... 7 CHAPTER 2 ....................................................................................................................10 LITERATURE REVIEW ...................................................................................................10 2.1 INTRODUCTION .........................................................................................................10 2.2 INCIDENCE ...............................................................................................................10 2.3 SYMPTOMS ..............................................................................................................11 2.4 PATHOLOGY .............................................................................................................11 2.5 ETIOLOGY ................................................................................................................13 2.5.1 Environmental Factors .....................................................................................13 2.5.2 Genetic Factors ................................................................................................15 2.6 MECHANISMS OF NEURODEGENERATION ....................................................................15 2.6.1 Oxidative Stress ...............................................................................................15 2.6.2 Altered mitochondrial function ..........................................................................18 2.6.3 Altered Proteolysis ...........................................................................................18 2.6.4 Inflammatory Change .......................................................................................19 2.6.5 Excitotoxic Mechanisms ...................................................................................19 2.6.6 Apoptosis .........................................................................................................19 2.7 TREATMENT .............................................................................................................19 2.7.1 Symptomatic Treatment ...................................................................................19 2.7.2 Neuroprotective Drugs .....................................................................................24 2.8 MONOAMINE OXIDASE...............................................................................................27 i 2.8.1 General Background ........................................................................................27 2.8.2 Biological Function of MAO ..............................................................................28 2.8.3 Tissue Distribution ...........................................................................................30 2.8.4 General Structure of MAO ................................................................................30 2.8.5 Mechanism of Action of MAO ...........................................................................36 2.8.6 MAO-A in depression and Parkinson’s disease ................................................39 2.8.7 MAO-B in Parkinson’s disease .........................................................................39 2.8.8 Irreversible Inhibitors of MAO-B .......................................................................40 2.8.9 Reversible Inhibitors of MAO-B ........................................................................44 2.8.10 Reversible Inhibitors of MAO-A ......................................................................44 2.8.11 Bifunctional Cholinesterase and MAO Inhibitors .............................................45 2.9 ANIMAL MODELS OF PARKINSON’S DISEASE ...............................................................45 2.9.1 MPTP mouse models .......................................................................................45 2.9.2 MPTP primate models ......................................................................................46 CHAPTER 3 ....................................................................................................................48 SYNTHESIS AND CHEMISTRY ......................................................................................48 3.1 INTRODUCTION .........................................................................................................48 3.2 CHEMISTRY ..............................................................................................................48 3.2.1 Results and Discussion ....................................................................................48 3.3 EXPERIMENTAL .........................................................................................................59 3.3.1 Materials and Instrumentation ..........................................................................59 3.3.2 Synthetic Procedures .......................................................................................62 3.3.3 Physical and Spectroscopic data of synthesized compounds ...........................63 3.4 SUMMARY ................................................................................................................72 CHAPTER 4 ....................................................................................................................73 BIOLOGICAL EVALUATION ..........................................................................................73 4.1 INTRODUCTION .........................................................................................................73 4.2 ENZYME KINETICS ....................................................................................................73 4.2.1 Competitive Inhibition .......................................................................................75 4.2.2 Non-competitive Inhibition ................................................................................76 4.2.3 Ki Determination ...............................................................................................76 4.2.4 IC50 Determination and its relationship to Ki .....................................................77 4.3 IC50 VALUE DETERMINATION OF THE TEST INHIBITORS ...............................................78 4.3.1 Chemicals and Instrumentation ........................................................................79 4.3.2 Method: IC50 value determination .....................................................................79 ii 4.3.3 Results and Discussion (IC50 determination) ....................................................80 4.4 MODE OF MAO INHIBITION .........................................................................................85 4.4.1 Construction of Lineweaver-Burk Plots ............................................................85 4.4.2 Results and Discussion (Mode of Inhibition) .....................................................86 4.5 REVERSIBILITY STUDIES FOR MAO INHIBITION USING DIALYSIS ..................................87 4.5.1 Dialysis ............................................................................................................87
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