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A preclinical covalent compound, CMX410, contains a aryl fluorosulfate warhead that targets the acyltransferase domain of Mtb Pks13, an essential enzyme in cell-wall biosynthesis, making it a promising candidate for tuberculosis treatment regimens.

Sulfur(vi) fluoride exchange (SuFEx)—a type of click chemistry that generates S^VI-centred covalent linkages—has previously been used for polymer synthesis. Now, modular SuFEx polymerization using SOF₄ has been used to generate helical polymers. Unlike previous examples of SuFEx polymerization, the backbone retains S^VI–F motifs and therefore is able to undergo further SuFEx click reactions, enabling facile and efficient post-polymerization modification.

The ambiphilic reactivity of alkyl sulfonyl fluorides in stereoselective cyclopropanation under Pd(II) catalysis is reported. The method provides convenient access to cis-disubstituted cyclopropanes that are otherwise challenging to access. A representative carboxylic acid cyclopropane building block is scaled up to 100 mmol, demonstrating the practicality of this transformation.

The organizing principles of click chemistry help scientists make molecules for a variety of applications. Such democratization of synthesis is challenging and rewarding, as useful simplicity is difficult to achieve. We reflect on this and look forward, hoping to continue to tie the joy of functional discovery to the challenges of synthetic chemistry.

Developing heat-resistant dielectric polymers for electrification is challenging due to the inverse relationship between thermal stability and electrical insulation. Using a machine learning-driven approach, the researchers identify and validate high-performance polymers that demonstrate promising thermal resilience and energy density for high-temperature applications.

Both click chemistry and polymer synthesis require reliable transformations with high selectivity, efficiency and fidelity. Now, bifluoride salts can be used as powerful catalysts for the sufur(VI) fluoride exchange (SuFEx) click reaction and they are applied to the synthesis of polysulfates and polysulfonates in a practical and scalable manner.

Glycan molecules can be modified directly on the cell surface via chemoenzymatic approaches. Here, the authors employ a set of four bacterial glycosyltransferases to develop a live cell-based killing assay to probe host cell glycan-mediated influenza A virus infection.

Latent functional groups—typically unreactive unless activated by protein binding—can provide additional selectivity to covalent drugs. Now, compounds containing the weakly electrophilic sulfuramidimidoyl fluoride group, capable of undergoing sulfur(vi) fluoride exchange, have been used to identify reactive proteins in human cell lysate. This approach has identified a compound that conjugates to and inhibits an important anticancer target.

Sulfur fluoride exchange (SuFEx) is a click reaction used to rapidly synthesize and discover functional molecules. In this Primer, Homer et al. discuss the essential elements of SuFEx operation, catalysis and SuFExable connective hubs and explore applications of SuFEx in drug development, polymer science and biochemistry.

There has been a resurgence of interest in the use of phenotypic screens in drug discovery as an alternative to target-focused approaches. Moffat and colleagues investigated the contribution of phenotypic assays in oncology by analysing the origins of the new small-molecule cancer drugs approved by the US Food and Drug Administration over the past 15 years. They also discuss technical and biological advances that could empower phenotypic drug discovery in oncology by enabling the development of mechanistically informed phenotypic screens.

Interrupting a reaction reroutes the outcome of a known chemical process. This Review highlights advances that enable the redirection of common intermediates in organic chemistry to new outcomes.

Microwave-assisted organic synthesis has considerable potential to accelerate the generation and optimization of lead compounds. Kappe and Dallinger outline the fundamental principles of this technology and discuss its applications in drug discovery.