Researchers at Vilnius University (VU) have developed a visible-light photoredox method that could help medicinal chemists rapidly generate new drug analogues from simple aromatic compounds.
The approach, published in the Journal of the American Chemical Society (JACS), enables a one-carbon fragment to be introduced directly into unactivated aromatic C-H bonds in a single step.
The resulting intermediate can then be converted into a range of different functional groups, allowing multiple molecular variants to be accessed without developing a separate synthetic route for each compound.
The VU team describes the intermediate as a chemical ‘adapter.’
Once installed, it provides a versatile handle for subsequent C-C and C-heteroatom bond formation, enabling access to substituted methyl-containing molecules.
The researchers demonstrated the method on several pharmaceutical and biologically active molecules, including ibuprofen, naproxen, a sildenafil analogue, cannabinoids, tadalafil derivatives and estrone.
This suggests the chemistry can tolerate functional groups present in relatively complex drug-like structures.
The method uses visible light to activate a photocatalyst, which transfers an electron to a methylenedipyridinium salt.
This generates the reactive species required to functionalise the aromatic ring. According to the researchers, the photocatalyst is used at just 1 mol % and the reaction does not require an external oxidant or reductant.
The work sits within the broader development of late-stage C-H functionalisation, an area of synthetic chemistry that has become increasingly relevant to drug discovery because it can enable structural diversification without requiring extensive rebuilding of a molecule.
Reviews of the field have highlighted its potential to improve the efficiency of medicinal chemistry programmes and accelerate the generation of drug-like analogues.
The VU researchers say the new platform could therefore be used to explore structure-activity relationships more rapidly, as well as in areas including mitochondrial targeting, molecular imaging and materials science.
The team added that they now plan to expand the reaction to a wider range of pharmaceutical molecules and investigate its mechanism and selectivity in more complex substrates.
