New MraY Inhibitors with an Aminoribosyl Uridine Structure and an Oxadiazole.

New inhibitors of the bacterial transferase MraY from (MraY), based on the aminoribosyl uridine central core of known natural MraY inhibitors, have been designed to generate interaction of their oxadiazole linker with the key amino acids (H324 or H325) of the enzyme active site, as observed for the highly potent inhibitors carbacaprazamycin, muraymycin D2 and tunicamycin. A panel of ten compounds was synthetized notably thanks to a robust microwave-activated one-step sequence for the synthesis of the oxadiazole ring that involved the -acylation of an amidoxime and subsequent cyclization. The synthetized compounds, with various hydrophobic substituents on the oxadiazole ring, were tested against the MraY transferase activity.

A Sub-Micromolar MraY Inhibitor with an Aminoribosyl Uridine Structure and a (,)-Tartaric Diamide: Synthesis, Biological Evaluation and Molecular Modeling.

New inhibitors of the bacterial tranferase MraY are described. Their structure is based on an aminoribosyl uridine scaffold, which is known to be important for the biological activity of natural MraY inhibitors. A decyl alkyl chain was introduced onto this scaffold through various linkers.

Synthesis, biological evaluation and molecular modeling of urea-containing MraY inhibitors.

The straightforward synthesis of aminoribosyl uridines substituted by a 5'-methylene-urea is described. Their convergent synthesis involves the urea formation from various activated amides and an azidoribosyl uridine substituted at the 5' position by an aminomethyl group. This common intermediate resulted from the diastereoselective glycosylation of a phthalimido uridine derivative with a ribosyl fluoride as a ribosyl donor.

Bacterial Transferase MraY, a Source of Inspiration towards New Antibiotics.

The bacterial resistance to antibiotics constitutes more than ever a severe public health problem. The enzymes involved in bacterial peptidoglycan biosynthesis are pertinent targets for developing new antibiotics, notably the MraY transferase that is not targeted by any marketed drug. Many research groups are currently working on the study or the inhibition of this enzyme.

Effect of uridine protecting groups on the diastereoselectivity of uridine-derived aldehyde 5'-alkynylation.

The 5'-alkynylation of uridine-derived aldehydes is described. The addition of alkynyl Grignard reagents on the carbonyl group is significantly influenced by the 2',3'-di--protecting groups (R): -alkyl groups led to modest diastereoselectivities (65:35) in favor of the 5'-isomer, whereas -silyl groups promoted higher diastereoselectivities (up to 99:1) in favor of the 5'-isomer. A study related to this protecting group effect on the diastereoselectivity is reported.

5'-Methylene-triazole-substituted-aminoribosyl uridines as MraY inhibitors: synthesis, biological evaluation and molecular modeling.

The straightforward synthesis of 5'-methylene-[1,4]-triazole-substituted aminoribosyl uridines is described. Two families of compounds were synthesized from a unique epoxide which was regioselectively opened by acetylide ions (for compounds II) or azide ions (for compounds III). Sequential diastereoselective glycosylation with a ribosyl fluoride derivative, Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) with various complementary azide and alkyne partners afforded the targeted compounds after final deprotection.

A diastereoselective synthesis of 5'-substituted-uridine derivatives.

A straightforward strategy for the synthesis of 5'-substituted-uridine derivatives is described. It relies on the introduction of various substituents at C-5' at the last step of the synthesis by regioselective nucleophilic opening of a unique epoxide that provides access to a small library of compounds. This epoxide results from the diastereoselective epoxidation, performed at a multigram scale, of a uridine-derived alkene.

Toward analogues of MraY natural inhibitors: synthesis of 5'-triazole-substituted-aminoribosyl uridines through a Cu-catalyzed azide-alkyne cycloaddition.

A straightforward strategy for the synthesis of triazole-containing MraY inhibitors has been developed. It involves the sequential introduction of a terminal alkyne at the 5' position of an uridine derivative and O-glycosylation with a protected aminoribose leading to an elaborated alkyne scaffold. An efficient Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) allowed the introduction of chemical diversity toward a small library of inhibitors.

Stereoselective synthesis of new chiral N-tertiary tetrasubstituted beta-enamino ester piperidines through an ammonia-catalyzed process.

We report here two approaches for the preparation of new N-substituted beta-enamino ester piperidines featuring an exocyclic tetrasubstituted double bond, based either on the direct alkylation of piperidine beta-enamino esters bearing an exocyclic trisubstituted double bond or on the intramolecular cyclization of linear amino beta-keto esters. The target compounds were obtained as unusual (Z)-stereoisomers in high yields. The key role of ammonia as reagent, acting both as a nucleophile and a base, was underlined.