Recent advances in Fragment-based strategies against tuberculosis.

Tuberculosis remains one of the world's leading infectious disease killers, causing more than 1.5 million of deaths each year. It is therefore a priority to discover and develop new classes of anti-tuberculosis drugs to design new treatments in order to fight the increasing burden of resistant-tuberculosis. Fragment-based drug discovery (FBDD) relies on the identification of small molecule hits, further improved to high-affinity ligands through three main approaches: fragment growing, merging and linking. The aim of this review is to highlight the recent progresses made in fragment-based approaches for the discovery and development of Mycobacterium tuberculosis inhibitors in a wide range of pathways. Hit discovery, hit-to-lead optimization, SAR and binding mode when available are discussed.

Rapid and Efficient Access to Novel Bio-Inspired 3-Dimensional Tricyclic SpiroLactams as Privileged Structures via Meyers' Lactamization.

The concept of privileged structure has been used as a fruitful approach for the discovery of novel biologically active molecules. A privileged structure is defined as a semi-rigid scaffold able to display substituents in multiple spatial directions and capable of providing potent and selective ligands for different biological targets through the modification of those substituents. On average, these backbones tend to exhibit improved drug-like properties and therefore represent attractive starting points for hit-to-lead optimization programs. This article promotes the rapid, reliable, and efficient synthesis of novel, highly 3-dimensional, and easily functionalized bio-inspired tricyclic spirolactams, as well as an analysis of their drug-like properties.

Intramolecular Palladium-Catalyzed Carboamination for the Stereoselective Synthesis of Five-Membered Iminosugar C-Glycosides.

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-C-arylmethyl substituent was obtained, and some of them were fully deprotected to yield original iminosugar C-glycosides. This methodology provides one of the shortest pathways to this family of molecules.

Tricyclic SpiroLactams Kill Mycobacteria In Vitro and In Vivo by Inhibiting Type II NADH Dehydrogenases.

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.

On the Hunt for Next-Generation Antimicrobial Agents: An Online Symposium Organized Jointly by the French Society for Medicinal Chemistry (Société de Chimie Thérapeutique) and the French Microbiology Society (Société Française de Microbiologie) on 9-10 December 2021.

The restrictions posed by the COVID-19 pandemic obliged the French Society for Medicinal Chemistry (Société de chimie thérapeutique) and the French Microbiology Society (Société Française de Microbiologie) to organize their joint autumn symposium (entitled "On the hunt for next-generation antimicrobial agents") online on 9-10 December 2021. The meeting attracted more than 200 researchers from France and abroad with interests in drug discovery, antimicrobial resistance, medicinal chemistry, and related disciplines. This review summarizes the 13 invited keynote lectures. The symposium generated high-level scientific dialogue on the most recent advances in combating antimicrobial resistance. The University of Lille, the Institut Pasteur de Lille, the journal Pharmaceuticals, Oxeltis, and INCATE, sponsored the event.

Aziridination of Cyclic Nitrones Targeting Constrained Iminosugars.

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.