Assessing the Optimal Deoxygenation Pattern of Dodecyl Glycosides for Antimicrobial Activity Against Bacillus anthracis

Abstract

The discovery of the bactericide dodecyl 2,6‐dideoxypyranoside reorganizing membrane phospholipid matrix of Bacillus species into a hexagonal phase, encouraged further research on glycone deoxygenation/bioactivity relationship. We now describe expedient syntheses of new 2‐, 3‐, 4‐deoxy, 2,3‐ and 3,4‐dideoxy glycosides in moderate to good yields. Interestingly, Amberlyst 15 is a key protagonist, efficiently applied for the transacetalation of alkyl deoxy glycosides and for ring contraction to access regioselectively hexofuranosides. The 2‐deoxy‐d‐arabino pyranoside affords the higher MIC values against two Bacillus spp. and Enterococcus faecalis, while a 4‐fold decrease or higher was found by inversion of configuration or by deoxygenation at C‐3. While 2,3‐ and 3,4‐dideoxygenation do not improve bioactivity, the 4,6‐dideoxy‐α‐d‐xylo‐hexopyranoside remains a promising glycoside, presenting low MIC values for all species tested, and low cytotoxicity in intestinal and liver cell models.

Isopropyl 3-deoxy-α-D-ribo-hexopyranoside (isopropyl 3-deoxy-α-D-glucopyranoside): evaluating trends in structural parameters

“…The resulting mixture was extracted twice with ethyl acetate (2 Â 40 ml) and the organic phases were combined and concentrated at 303 K in vacuo to give 1,2:5,6-di-O-isopropylidene-3-deoxy--d-ribo-hexofuranose, (VII), as a colorless oil in 74% yield (1.22 g, 5.0 mmol). NMR spectral data obtained for (VII) were consistent with those reported previously (Dias et al, 2019). Dowex 50 Â 8 (200-400 mesh) ion-exchange resin (H + form) (3 g, dry weight) was added to a solution of (VII) (1.22 g, 5.0 mmol) in isopropyl alcohol (50 ml) and the resulting mixture was refluxed at 373 K for 24 h. The reaction mixture was cooled and the resin was removed by filtration.…”

“…The organic phases were combined and concentrated at 303 K in vacuo to give 1,2:5,6-di-O-isopropylidene-3-O-triflyl--d-ribo-hexofuranose, (VI), as a yellow solid in nearly quantitative yield (3.0 g, 7.7 mmol). NMR spectral data obtained for (VI) were consistent with those reported previously (Dias et al, 2019;Russell et al, 1990).…”

“…Isopropyl 3-deoxy--d-ribo-hexopyranoside (isopropyl 3-deoxy--d-glucopyranoside), (I), was prepared from 1,2:5,6-di-O-isopropylidene--d-glucofuranose (Dias et al, 2019) and crystallized from a mixture of methanol and ethyl acetate at room temperature to give colorless tablet-like crystals devoid of solvent (Fig. 2).…”

Recent Advances in the Development and Synthesis of Carbohydrate‐Based Molecules with Promising Antibacterial Activity

“…Among the most promising compounds reported, compound 7 (Scheme 1) stood out as the bactericide with the lowest minimum inhibitory concentration (MIC) against all tested species, including Bacillus anthracis Sterne, pathogenic and ovine strains, as well as Enterococcus feacalis and Bacillus cereus (MIC 12.6 μM for all), and acceptable toxicity in intestinal and hepatic cell models after a 48 hour-long exposure (IC 50 50 μM in Caco-2 cells and > 100 μM in HepG2 cells, respectively). [25,26] Further studies suggested that this class of compounds has a low propensity for the development of AMR mechanisms induced by serial passage on gradient concentrations, as well as low susceptibility to common resistance mechanisms against erythromycin, penicillin, vancomycin, ciprofloxacin, and tetracycline. With a relatively good therapeutic window corroborated by the observed selectivity of these compounds towards PE compared to phosphatidylcholine (PC) -the main phospholipid in mammalian membranes, the 4,6deoxygenation pattern of compound 7 was considered the key Scheme 1.…”

Stereoselective synthesis of alkyl pyranosides on a laboratory scale

“…Their cytotoxicity, however, increases with an increasing chain length of the aglycon 10 . The number of reports dealing with the antimicrobial activity of alkyl glycosides is rare [13][14][15][16] .…”