Synthesis of Arabino glycosyl triazoles as potential inhibitors of mycobacterial cell wall biosynthesis Brendan L. Wilkinson a , Hilary Long b , Edith Sim b , Antony J. Fairbanks a, * a Department of Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK b Department of Pharmacology, Oxford University, Mansfield Road, Oxford OX1 3QT, UK article info Article history: Received 3 September 2008 Revised 22 September 2008 Accepted 23 September 2008 Available online 26 September 2008 Keywords: Carbohydrates Glycosyl triazoles Click chemistry Arabinose Mycobacteria Tuberculosis abstract A series of arabino glycosyl triazoles with varying hydrophobic groups were synthesised as putative mim- ics of decaprenolphosphoarabinose (DPA) as potential inhibitors of mycobacterial cell wall biosynthesis. Biological testing against Mycobacterium bovis BCG revealed low to moderate anti-mycobacterial activity, with strong dependence on the identity of the hydrophobic side chain. Ó 2008 Elsevier Ltd. All rights reserved. Inhibition of mycobacterial cell wall biosynthesis represents a significant therapeutic opportunity for the development of new anti-tubercular agents. 1 The cell walls of mycobacteria are com- plex, and there are therefore many biosynthetic steps that could in principle be targeted in order to compromise mycobacterial via- bility. Two cell wall polysaccharides that are unique to mycobacte- ria and which are crucial to mycobacterial survival and growth are lipoarabinomannan (LAM) and arabinogalactan (AG). Inhibition of the biosynthesis of either LAM or AG represents a potentially highly selective opportunity for therapeutic intervention, and the design and synthesis of such potential inhibitors has been a field of intense interest over recent years. Approaches have included 2 attempted inhibition of various glycosyl transferases 3 used for polysaccharide assembly, and also of other vital biosynthetic en- zymes such as the Galp/Galf mutase which catalyses a crucial pyra- nose/furanose isomerisation during assembly of the galactan cell wall component. 4 Particular interest has focused on the attempted discovery 5 of potent inhibitors of arabinosyl transferases, which are responsible for the stepwise assembly of the arabinan portions of both LAM and AG, and use decaprenol phosphoarabinose 1 (DPA, Fig. 1) as the glycosyl donor. Metabolically stable analogues of DPA may in- hibit these arabinosyl transferases, and so in turn represent lead compounds for the discovery of new anti-tubercular agents. In or- der to design mimics of DPA that may be expected to display useful in vivo activity, two immediate considerations present themselves. Firstly replacement of the labile glycosyl phosphate with a stable isostere would be highly desirable. Secondly it may be expected that an alkyl chain of a certain minimum length would be required to mimic the large hydrophobic decaprenyl moiety of DPA. Various isosteric replacements for the glycosyl phosphate have been inves- tigated 6 including b-C-glycosyl sulfones and b-C-phosphonates. Amongst several approaches 7 to inhibition of mycobacterial arab- inan biosynthesis under investigation in this laboratory the poten- tial use of a b-glycosyl triazole as the replacement for the glycosyl phosphate moiety of DPA appeared to be an attractive line of inves- tigation. 8 The discovery that Cu(I) salts can efficiently catalyse the Huisgen 1,3-dipolar cycloaddition of alkynes and azides, reported simultaneously 9 by Meldal and Sharpless, has led to a resurgence in interest in the triazole functional group, and has popularised its use as an isosteric replacement in lead generation programs. In- deed this particular application of ‘Click chemistry’ 10 has become one of the mainstays of currently favoured approaches for the 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.09.082 * Corresponding author. Tel.: +44 1865 275647; fax: +44 1865 275674. E-mail address: antony.fairbanks@chem.ox.ac.uk (A.J. Fairbanks). O OH HO O HO 1 P O O 9 O Figure 1. Decaprenolphosphoarabinose 1 (DPA). Bioorganic & Medicinal Chemistry Letters 18 (2008) 6265–6267 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl