High-Throughput Experimentation Enables the C6-Functionalisation of 1H-Indazol-3-Amines as Antitubercular Agents
- 1Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstr. 48, Münster, Germany, 48149
- 2Department of Preclinical Imaging and Radiopharmacy, Cluster of Excellence iFIT (EXC 2180) “Image-guided and Functionally Instructed Tumor Therapies, Roentgenweg 13, Tuebingen, Germany, 72076
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.
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BibTeX
@misc{janssen2026highthroughput,
title = {{High-Throughput Experimentation Enables the C6-Functionalisation of 1H-Indazol-3-Amines as Antitubercular Agents}},
author = {Philipp Janssen and Fabrice Becker and Vesa Krasniqi and Sophia Gethmann and Anna Junker and Oliver Koch},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008508/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008508/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - High-Throughput Experimentation Enables the C6-Functionalisation of 1H-Indazol-3-Amines as Antitubercular Agents
AU - Philipp Janssen
AU - Fabrice Becker
AU - Vesa Krasniqi
AU - Sophia Gethmann
AU - Anna Junker
AU - Oliver Koch
PY - 2026
DA - 2026/09/08
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008508/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008508/v1
AB - 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.
ER -