Journal Article

Nitroreductase-triggered indazole formation

Chernyshova, Elizaveta, Poelarends, Gerrit J., Schmidt, Sandy, Prats Luján, Alejandro, Terholsen, Henrik, Medema, Lisa

2026

Overview

Biocatalysis contributes significantly to the development of more sustainable synthetic pathways by using mild reaction conditions and water as a solvent. However, many relevant classes of compounds, including privileged groups in drug design, are not yet accessible via enzymatic pathways. In this context, the development of an enzymatic route to indazoles remains an unmet challenge. Here, we present a nitroreductase-triggered indazole formation, in which 2-nitrobenzylamine derivatives are converted to reactive nitrosobenzylamine intermediates that spontaneously cyclize and aromatize to indazoles. Two nitroreductases accept a series of 2-nitrobenzylamine derivatives with excellent conversions (up to >99 %). In the case of N -substituted nitrosobenzylamines, 2 H -indazoles are formed, whereas other derivatives led to 1 H -indazoles. The synthetic value of the nitroreductase-triggered indazole formation is further demonstrated by successful coupling with an imine reductase in a sequential cascade reaction on a 50 mg scale. With this cascade, 2 H -indazoles are accessible from cheap 2-nitrobenzaldehyde and primary amines, resulting in up to 85 % conversion and 68 % isolated yield. An enzymatic route to indazoles, scaffolds present in many drugs, has not been developed yet. Here, the authors report nitroreductase-triggered indazole formation, in which 2-nitrobenzylamine derivatives are converted to reactive nitrosobenzylamine intermediates that spontaneously cyclize and aromatize to indazoles.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 140/131 / 140/58 / 631/45/607 / 639/638/77/603 / 82/80 / 82/83 / Accessibility / Amines / Benzaldehydes / Benzylamines - chemistry / Benzylamines - metabolism / Biocatalysis / Cascade chemical reactions / Catalysis / Chromatography / Cyclization / Drug development / Enzymes / Experiments / Glucose / Humanities and Social Sciences / Indazoles - chemical synthesis / Indazoles - chemistry / Indazoles - metabolism / Intermediates / multidisciplinary / Nitroreductase / Nitroreductases - chemistry / Nitroreductases - metabolism / Reductases / Science / Science (multidisciplinary) / Sustainable development