Accessing Active Fragments for Drug Discovery Utilising Nitroreductase Biocatalysis

Biocatalysis has played a limited role in the early stages of drug discovery. This is often attributed to the limited substrate scope of enzymes not affording access to vast areas of novel chemical space. Here, we have shown a promiscuous nitroreductase enzyme (NR‐55) can be used to produce a panel of functionalised anilines from a diverse panel of aryl nitro starting materials. After screening on analytical scale, we show that sixteen substrates could be scaled to 1 mmol scale, with several poly‐functional anilines afforded with ease under the standard conditions. The aniline products were also screened for activity against several cell lines of interest, with modest activity observed for one compound. This study demonstrates the potential for nitroreductase biocatalysis to provide access to functional fragments under benign conditions. Holder et al. show a promiscuous nitroreductase biocatalyst can afford access to a panel of functionally diverse aniline fragments. These have been shown to be active in biological assays, offering a route to a biocatalysis‐derived fragment space for novel bioactive molecules.