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Investigations Into Sulfamide As a Phosphate Isostere in Anti-TB Drug Development

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Investigations Into Sulfamide As a Phosphate Isostere in Anti-TB Drug Development Investigations into sulfamide as a phosphate isostere in anti-TB drug development A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry at the University of Canterbury Kajitha Suthagar Supervisor: Prof. Antony Fairbanks University of Canterbury 2017 Table of contents Abstract ................................................................................................................. iv Acknowledgements ................................................................................................................. vi Abbreviations .............................................................................................................. viii Chapter 1 Introduction ....................................................................................................... 1 1.1 General introduction ............................................................................................... 1 1.2 Biological background ........................................................................................... 1 1.2.1 General aspects of tuberculosis ............................................................................ 1 1.2.2 Cell wall structure of M. tuberculosis .................................................................. 5 1.2.3 Arabinan biosynthesis .......................................................................................... 9 1.2.3.1 Arabinofuranosylsyltransferases ..................................................................... 10 1.3 The design of DPA analogues as inhibitors of arabinofuranosyltransferases ............................................................................... 14 1.4 Design dTMP analogues as inhibitors of dTMPK ................................................ 27 1.4.1 De novo and salvage pathways .......................................................................... 27 1.4.2 Deoxythymidine monophosphate kinase (TMPK) ............................................ 28 1.4.3 The dTMP binding site of TMPKmt .................................................................. 29 1.4.4 Previous work on the design and synthesis of inhibitors of TMPKmt .............. 31 1.5 Project objectives .................................................................................................. 37 Chapter 2 The synthesis of DPA analogues as anti-TB agents. ..................................... 39 2.1 Introduction ........................................................................................................... 39 2.2 The synthesis of glycosyl sulfamides and anti-mycobacterial activities .............. 44 2.2.1 Retrosynthetic analysis ...................................................................................... 44 2.2.2 Synthesis of the arabinose donor 2.6 ................................................................. 45 2.2.3 Synthesis of sulfamide acceptors ....................................................................... 46 2.2.4 Synthesis of sulfamidoglycosides ...................................................................... 50 2.3 Synthesis of arabinose N-glycosyl sulfonamides and sulfamates ......................... 59 i 2.4 Screening of final compounds as anti-tuberculosis agents ................................... 61 2.5 Synthesis of N-glycosyl sulfamides lacking a 5-hydroxyl group ......................... 69 2.5.1 Synthetic strategy ............................................................................................... 69 2.5.2 Biological activity .............................................................................................. 73 2.6 Conclusions ........................................................................................................... 75 Chapter 3 Synthesis of thymidine monophosphate analogues as potential inhibitors of mycobacterial cell wall biosynthesis ............................. 76 3.1 Introduction ........................................................................................................... 76 3.2 Molecular docking and structure-based drug design of thymidine monophosphate analogues ................................................................................... 78 3.2.1 Docking preparation and settings....................................................................... 78 3.2.2 Induced fit docking of the target sulfamide derivatives ...................................... 80 3.3 Synthesis of sulfamide derivatives as dTMP analogues ...................................... 84 3.3.1 Retrosynthetic analysis ...................................................................................... 84 3.3.2 The synthesis of sulfamoyl chlorides .................................................................. 86 3.3.3 The synthesis of target sulfamide derivatives. .................................................... 87 3.4 Biological activity of the sulfamide analogues of dTMP ..................................... 88 3.5 Conclusions ........................................................................................................... 90 3.6 Future work ........................................................................................................... 90 Chapter 4 Efficient reduction of organic azides by sodium iodide in the presence of acidic ion exchange resin ................................................. 92 4.1 Introduction ........................................................................................................... 92 4.2 Optimization of the reduction conditions ............................................................. 94 4.3 Synthesis of azides for reduction. ....................................................................... 100 4.4 Reduction of azides to primary amines with different functional groups ........... 101 4.5 Conclusions ......................................................................................................... 104 Chapter 5 Experimental section ..................................................................................... 105 5.1 General chemical experimental........................................................................... 105 ii 5.2 Experimental for chapter 2 .................................................................................. 106 5.3 Experimental for chapter 3 .................................................................................. 186 5.4 AB assay Protocol ............................................................................................... 196 5.4.1 Preparation of Growth Medium ....................................................................... 196 5.4.1.1 Lysogeny Broth (LB) and LB/Tween 80 (LB/T) ........................................... 196 5.4.1.2 LB Agar ........................................................................................................ 196 5.4.1.3 Glycerol Freezer Stocks ................................................................................ 196 5.4.2 Preparation of M. smegmatis stocks: ............................................................... 197 5.4.3 Determine CFU/mL of Freezer Stocks ............................................................ 197 5.4.4 Assay plates: .................................................................................................... 198 References .............................................................................................................. 212 iii Abstract Two major oligosaccharides, lipoarabinomannan (LAM) and arabinogalactan (AG), are important constituents of the cell wall of Mycobacterium tuberculosis, the causative bacterial pathogen of tuberculosis. The AG, which is attached to long chain lipids, provides a very effective hydrophobic barrier against the penetration of anti- mycobacterial drugs. The LAM and AG consist of varying numbers of arabinofuranose residues. The biosynthesis of the arabinan portion of both is postulated to involve multiple arabinofuranosyltransferases (AraT's), which catalyse the step-wise coupling of the donor decaprenolphosphoarabinose (DPA) to growing oligosaccharides. We have synthesized a series of arabino glycosyl sulfamides as potential inhibitors of mycobacterial cell wall biosynthesis. In this work sulfamide was used as an isostere of phosphate and varied the hydrophobic substituents as mimics of the polyprenol chain of DPA. However, arabino N-glycosyl sulfamides, sulfonamides, and sulfamates unexpectedly and spontaneously converted from the furanose to the pyranose form in an aqueous solution. To remedy this, a series of glycosyl sulfamides which lacked the 5-hydroxyl group were synthesized in order to fix these materials in the furanose form. All compounds were synthesised and tested for anti-mycobacterial activity using the Alamar Blue (AB) assay. Compounds displayed low to moderate activity against M. smegmatis. The recently discovered enzyme Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt), catalyses the phosphorylation of thymidine monophosphate (dTMP) to give thymidine diphosphate (dTDP), and is indispensable for the growth and survival of M. tuberculosis, as it plays an essential role in the DNA synthesis. Therefore, inhibition of TMPKmt may be an attractive avenue for the iv development of novel anti-tuberculosis agents. Possible sulfamide structures were screened using in silico induced-fit docking methods as dTMP analogues with TMPKmt X-ray crystal structure (PDB accession code: 1N5K). From these docking results, a selection
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