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International audience; It is critical that novel classes of antituberculosis drugs are developed to combat the increasing burden of infections by multidrug-resistant strains. To identify such a novel class of antibiotics, a chemical library of unique 3-D bioinspired molecules was explored revealing a promising, mycobacterium specific Tricyclic SpiroLactam (TriSLa) hit. Chemical optimization of the TriSLa scaffold delivered potent analogues with nanomolar activity against replicating and nonreplicating Mycobacterium tuberculosis. Characterization of isolated TriSLa-resistant mutants, and biochemical studies, found TriSLas to act as allosteric inhibitors of type II NADH dehydrogenases (Ndh-2 of the electron transport chain), resulting in an increase in bacterial NADH/NAD+ ratios and decreased ATP levels. TriSLas are chemically distinct from other inhibitors of Ndh-2 but share a dependence for fatty acids for activity. Finally, in vivo proof-of-concept studies showed TriSLas to protect zebrafish larvae from Mycobacterium marinum infection, suggesting a vulnerability of Ndh-2 inhibition in mycobacterial infections.

We report here a new method for the stereoselective synthesis of five-membered iminosugar C-glycosides using an intramolecular palladium-catalyzed carboamination. We have prepared efficiently two sugar-derived aminoalkenes, which were submitted to the carboamination conditions in the presence of different aryl bromides. A small library of protected iminosugars carrying a 1

The synthesis of the peracetylated ketonitrone 4 is described in four steps from L-sorbose. This cyclic nitrone is crystalline and proved to preferentially adopt a 4H3 conformation with all acetate groups in pseudo-axial orientation. Nitrone 4 undergoes regioselective cycloadditions with alkynes, affording tetra-O-acetyl-isoxazolines with good yields and stereoselectivities (4 : 1 to 9 : 1 diastereomeric ratio). Nitrone 4 and the obtained isoxazolines were smoothly deacetylated to produce the polyhydroxylated nitrone 5 and novel iminosugars containing an isoxazoline motif. Evaluation of their glycosidase inhibitory activity demonstrated their rather weak, but selective affinity for a variety of enzymes.

The Baldwin rearrangement is a thermally induced ring contraction of 4-isoxazolines into 2-acylaziridines. The reaction yields highly strained nitrogen-containing three-membered-ring compounds from readily available five-membered N-O heterocycles. Diversely substituted isoxazolines are directly transformed into a variety of highly functionalized 2-acylaziridines in a stereocontrolled process. In this review mechanistic aspects and stereoselectivity of this rearrangement are discussed. Although still undervalued, the Baldwin rearrangement may have significant applications in the synthesis of complex aziridine-containing targets such as natural products or pharmaceuticals.

Rare C-7-substituted aziridinyl iminosugars can be synthesized through a short reaction sequence involving 1,3-cycloaddition of cyclic nitrones with alkynes and a Baldwin rearrangement of isoxazolines into bicyclic 2-acylaziridines. The method is efficient and completely diastereoselective, producing stable aziridinyl iminosugars in high yields.