New inhibitors of the bacterial tranferase MraY are described. A scaffold strategy based on the diazepanone central core of liposidomycins, natural inhibitors of MraY has been developed. It involves ...the introduction of key structural fragments required for biological activity on enantiopure diazepanones by reductive amination, esterification and glycosylation. Biological evaluation of these compounds on MraY enzyme revealed interesting inhibitory activity for compounds displaying three fragments on the scaffold: a palmitoyl chain, an aminoribose part and an alkyluracil moiety. The inhibitors were also evaluated on MurG enzyme. The best compounds resulted in inhibition with IC
50 values in the 100 μM range for one or the other enzyme.
A straightforward route toward new MraY inhibitors is described. A scaffold strategy based on highly functionalized diazepanone platforms is developed. Biological evaluation of the compounds is reported.
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► A scaffold strategy was developed toward a library of MraY inhibitors. ► A diazepanone scaffold, central core of natural MraY inhibitors, was chosen. ► Fatty acid, alkyluracil and aminoribose were introduced on the scaffold. ► Biological evaluation showed inhibition of MraY activity with IC
50 in the 100 μM range.
Stable analogs of bacterial transferase MraY substrate or product with a pyrophosphate surrogate in their structure are described. β-ketophosphonates were designed as pyrophosphate bioisosteres and ...were investigated as UDP-GlcNAc mimics. The developed strategy allows introduction of structural diversity at a late stage of the synthesis. The biological activity of the synthesized compounds was evaluated on the MraY enzyme.
An efficient and convergent method for the synthesis of mannose-1-phosphate prodrugs is described as a potential therapy for congenital disorders of glycosylation-Ia (CDG-Ia). The key feature of the ...proposed approach is the silver assisted nucleophilic substitution of 2,3,4,6-tetra-
O-protected-α-
d-mannopyranosyl bromides with various silver phosphate salts to afford mono, di, and tri-mannopyranosyl phosphates. A preliminary biological evaluation of the synthesized phosphate prodrugs has been carried out.
New inhibitors of the bacterial transferase MraY are described. Their structure is based on an aminoribosyl-
O-uridine like scaffold, readily obtained in two key steps. The amino group can be coupled ...with proline or guanylated. Alternatively, these amino, prolinyl or guanidinyl groups can be introduced through a triazole linker. Biological evaluation of these compounds on MraY from
Bacillus subtilis revealed interesting inhibitory activity for both amino compounds.
The synthesis of polyfunctionalised enantiopure 1,4-diazepan-3-one scaffolds from
l-serine derivatives and azidoepoxides readily available from either
l-ascorbic or
d-isoascorbic acid, allowing ...access to various configurations at chiral centres, is described. The key steps are the nucleophilic opening of the epoxide by the amine of serine followed by a lactonisation–lactamisation sequence.
Herein we describe the synthesis of three new (7-methoxychromenonyl)methyl 2-N-propionyl-2′,3′-isopropylideneguanosine 5′-phosphate diesters, potentially photolabile nucleotides, via an H-phosphonate ...strategy. The stability of these compounds toward acidic and basic conditions was evaluated during the nucleoside moiety deprotection.
Glycosylation involving d-ribose derivatives and various N-protected tert-butyl l-serinates can be achieved efficiently by careful choice of the activation method at the anomeric position and of the ...Lewis acid promoter. The conditions described allow the major formation of the β-anomer required for further elaboration to liposidomycin and caprazamycin analogues.
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A series of 16 new chiral nonracemic polyhydroxylated piperidines was synthesized utilizing several chiral β-amino-alcohols. They act as a nitrogen source, chirality inducer and ...iminium stabilizer, in the desymmetrization of
meso-trihydroxylated glutaraldehyde. The biological activity of these compounds towards several glycosidases (α-
d-glucosidase, α-
d-mannosidase, α-
l-fucosidase) has been evaluated.
A synthesis of the enantiopure 2‐ribosyl‐1,4‐diazepan‐3‐one core of liposidomycins, a class of complex lipid nucleoside antibiotics, according to a flexible asymmetric synthesis strategy is ...described. It involves two building blocks, an enantiopure α‐azido‐β,γ‐epoxybutanol readily available from L‐ascorbic acid, and an α‐ribosylamino acid obtained from D‐ribose. Subsequent cyclization by regiospecific nucleophilic opening of the epoxide by the amino acid followed by peptidic coupling affords the target ribosyl diazepanone.
The synthesis of new enantiopure polyhydroxylated octahydroindoles and decahydroquinolines, analogs to castanospermine, via a double reductive amination of enantiopure cyclic ketoaldehyde, and their ...inhibitory activity against α- or β-
d-glucosidases, α-
d-mannosidase and α-
l-fucosidase are described.
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