High-Throughput Experimentation Enables the C6-Functionalisation of 1H-Indazol-3-Amines as Antitubercular Agents
Year: 2026
Type: preprint
Abstract: The development of novel antitubercular drugs targeting mycobacterial thioredoxin reductase (TrxR) has previously been hampered by the synthetic intractability of promising benzisothiazole-based inhibitors. Here, we identify 6-substituted 1H-indazol-3-amine as a bioisosteric scaffold that offers a comparable binding mode and improved synthetic accessibility. To address the lack of established protocols for the derivatisation of this scaffold at the C6 Position, we carried out a high-throughput experimentation (HTE) campaign with 984 individual reactions. Through parallel screening, the reaction condition space for Suzuki-Miyaura and Buchwald-Hartwig cross-couplings was systematically mapped, identifying a set of generally applicable conditions. Biochemical evaluation of the resulting library validated the bioisosteric design, yielding several derivatives with enhanced inhibitory activity against mycobacterial TrxR, including a micromolar inhibitor. Co-crystal structures of five derivatives could be obtained. This study establishes a synthetic foundation for exploring the 1H-indazol-3-amine scaffold and demonstrates how HTE can successfully address synthetic challenges in fragment-based drug discovery.
Source: ChemRxiv
Institution: University of Münster
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7211971705