Investigations into sulfamide as a phosphate isostere in anti-TB drug development.
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
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 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 of compounds was synthesized and the evaluated for any anti-mycobacterial activity. However, none of the compounds showed promising inhibitory activity against M. smegmatis.
A novel reduction method was accidentally discovered during the synthesis of 6-amino-D-mannose pyranose, using iodide and Amberlite IR 120 ion exchange resin (H⁺ form). During this process, D-mannose was first selectively iodinated using an Appel reaction, subsequent nucleophilic substitution using NaN3. Following that reaction, in order to remove the imidazole, the reaction mixture was filtered through Amberlite IR 120 ion exchange resin (H⁺ form), and then concentrated in vacuo. Interestingly, the final product was identified as the amine. As it is simple, efficient, and mild reduction method for the conversion of azides into amines, the reaction condition was optimized using NaI/Amberlite IR120 (H⁺ form), and tolerance of the functional groups also investigated.