Triazole‐Linked Iminosugars and Aromatic Systems as Simplified UDP‐Galf Mimics: Synthesis and Preliminary Evaluation as Galf‐Transferase Inhibitors

Abstract

The convenient preparation of 1,4‐dideoxy‐1,4‐imino‐l‐arabinitol derivatives bearing a propargyl group through the addition of a trimethylsilylpropargyl Grignard reagent to an N‐sulfinylglycosylamine is reported. One of these compounds was coupled by a triazole tether to various aromatic and heteroaromatic groups to give structures that can be considered to be simplified mimics of UDP‐Galf, the substrate of GlfT2, a galactofuranosyltransferase present in mycobacteria. The new compounds were evaluated as inhibitors of this enzyme and were found to have significant activity (IC50 values in the high µm to low mm range), despite the absence of the diphospho linkage present in the parent sugar nucleotide.

Biosynthesis of Galactan in Mycobacterium tuberculosis as a Viable TB Drug Target?

“…The efforts towards the identification of GlfT1 and GlfT2 inhibitors focused primarily on the design of transition state or substrate mimics [76,[101][102][103][104][105] (summarized in Table 2). The most active among these compounds was fluorinated exo-glycal analogue of UDP-Galf with IC 50 180 µM ( Table 2, Entry 8), established by a radiometric assay with crude cell wall enzyme fraction from M. smegmatis and O-alkyl β-d-Galf -(1→6)-β-d-Galf acceptor [102].…”

Glycoside Mimics from Glycosylamines: Recent Progress

“…The N - tert -butanesulfinyl glycosylamines undergo addition reactions with a range of Grignard and lithium reagents to give related 1,2- syn or 1,2- anti -aminoalditols in good yields and moderate to excellent diastereoselectivities [99,101,102,103]. Their reactivity was found to be similar to that of N -alkyl- N -glycosides and of N -benzyl- N -glycosylhydroxylamines with a chemical stability similar to that of the N -Cbz-analogues [99].…”

“…Thus, in such cases, the chiral N - tert -butanesulfinyl auxiliary does not direct the stereoselectivity at C-1. Importantly, however, the process can be scaled-up (up to 1.9 g of product 82 ) [102], without erosion of the diastereo-selectivity. The method was implemented to a variety of organomagnesium species (see Table 3) [99], including propargyl Grignard reagents [101].…”

“…Afterwards, the sulfinyl protecting group was removed with mild acid (HCl in MeOH) to generate the corresponding 1,2- cis imino- C -glycosyl derivatives 83 in good yields (see procedure C) [99,102]. Alternatively, the sulfinyl group may be cleaved first and cyclization promoted from the free amine, which occurs spontaneously (procedure D) [101,103].…”

“…The preparation of 1,4-dideoxy-1,4-imino- l -arabinitol scaffolds 84bE tethered to 1,2,3-triazoles carrying (hetero)aromatic systems as simplified uridinyl diphospho- d -galactofuranose (UDP-Gal f ) mimics were prepared by these methods through the addition of a trimethylsilylpropargyl Grignard reagent to N -sulfinylglycosylamine ( S R )- 81b , followed by cyclization/deprotection sequences (Scheme 28) [102]. Compound 84bE is a moderate inhibitor of GlFT2 , a key galactofuranosyltransferase involved in the assembly of the cell wall of mycobacteria (including the causative agent of tuberculosis, Mycobacterium tuberculosis ) [104], and it is essential for mycobacterial viability [105,106].…”