{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstr. 48, Münster, Germany, 48149",
    "Department of Preclinical Imaging and Radiopharmacy, Cluster of Excellence iFIT (EXC 2180) “Image-guided and Functionally Instructed Tumor Therapies, Roentgenweg 13, Tuebingen, Germany, 72076"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Philipp Janssen"
    },
    {
      "affs": [
        0
      ],
      "name": "Fabrice Becker"
    },
    {
      "affs": [
        0
      ],
      "name": "Vesa Krasniqi"
    },
    {
      "affs": [
        0
      ],
      "name": "Sophia Gethmann"
    },
    {
      "affs": [
        1
      ],
      "name": "Anna Junker"
    },
    {
      "affs": [
        0
      ],
      "name": "Oliver Koch",
      "orcid": "0000-0001-9228-217X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2vf4asnwr7y34.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15008508/v1",
  "fulltext_url": null,
  "id": "2vf4asnwr7y34",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008508/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1605|Synthesis and biological activity"
    ]
  ],
  "openalex": "W7211971705",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15008508/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-08",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/2vf4asnwr7y34.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:17Z",
      "native_id": "10.26434/chemrxiv.15008508",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008508/v1"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1605|Synthesis and biological activity",
      "subfield": "organic"
    }
  ],
  "title": "High-Throughput Experimentation Enables the C6-Functionalisation of 1H-Indazol-3-Amines as Antitubercular Agents",
  "title_text": "High-Throughput Experimentation Enables the C6-Functionalisation of 1H-Indazol-3-Amines as Antitubercular Agents",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:17Z",
  "url": "https://research.draconitic.com/paper/2vf4asnwr7y34",
  "venue": "ChemRxiv",
  "versions": []
}