Researchers at the Institute of Chemical Research of Catalonia (ICIQ), led by Prof. Marcos García Suero, have developed a new catalytic method that allows chemists to reshape the core structure of drug-like molecules without having to rebuild them from scratch. Published in ACS Catalysis, the work introduces a faster route to generate new molecular variants, a key step in the optimisation of potential medicines.
Developing a promising drug often requires making small changes to its molecular structure to improve how it behaves in the body. One common strategy is to replace the molecule’s central ring, while keeping the parts responsible for its biological activity unchanged. Until now, each new version usually had to be synthesised independently. The ICIQ team has developed a catalytic shortcut that directly remodels one of these rings, known as an isoxazole, into several other useful structures. It is comparable to replacing a car’s engine without opening the bonnet: instead of rebuilding the whole molecule, chemists can edit its core in just a few steps.
The new method is fast, operates under mild conditions and is compatible with complex molecules similar to those used in medicinal chemistry. This makes it particularly valuable for the later stages of drug development, when researchers need to prepare and test many closely related compounds to identify the best candidate.
“This methodology is fast, mild, and operationally simple; also, it is well suited to complex drug-like molecules and can be applied in late-stage scenarios. For lead optimisation campaigns, this means many distinct analogues from a single precursor, saving considerable time and resources,” says Matteo Balletti, first author of the study and postdoctoral researcher in Prof. Suero’s group. Leonardo Pagliano, PhD student and co-author, adds: “This could be a significant addition to the medicinal chemistry toolbox, as it could dramatically speed up the process of fine-tuning drug candidates.”
The strategy is based on a rhodium-catalysed reaction that inserts a single carbon atom into the molecular framework, opening the original ring and generating versatile intermediates that can be converted into several families of heterocycles commonly found in pharmaceuticals. The method showed broad applicability, high selectivity and compatibility with a wide variety of functional groups, demonstrating its potential as a practical new tool for medicinal chemistry and lead optimisation.
Reference publication
Scaffold Hopping of Isoxazole Enabled by an Oxidative Rh-Catalyzed Single-Carbon Insertion
Balletti, M.; Pagliano, L.; Suero, M. G.
ACS Catal. 2026
DOI: 10.1021/acscatal.6c02785
La entrada Direct scaffold editing for faster drug optimisation se publicó primero en ICIQ.