{
  "abstract": "2,3- and 2,4-Disubstituted 2-azabicyclo[3.n.1]alkanes (n = 1, 2) are introduced as bioisosteres of 1,2- and 1,3-disubstituted piperidines, respectively. The 2-azabicyclo[3.1.1]heptane and 2-azabicyclo[3.2.1]octane cores were constructed in a single step by a scalable intramolecular carbene N–H insertion, with subsequent functionalization giving α- and β-amino acids and other bifunctional derivatives amenable to two-point diversification. Structural analysis of the disubstituted 2-azabicyclo[3.1.1]heptane derivatives showed that both substitution patterns matched their reference piperidines in all exit vector parameters but one, and in that one occupied a geometry not observed for the parent ring. Virtual decoration of the functional groups on both 2-azabicyclo[3.n.1]alkane cores gave a library whose calculated physicochemical property profile coincided with that of the monocyclic reference, except for a modest increase in molecular weight. To validate the bioisosteric replacement in a biological context, conformationally restricted bupivacaine analogs based on both cores were prepared and evaluated in the mouse tail-flick assay. The 2-azabicyclo[3.1.1]heptane derivative reproduced the antinociceptive effect ofthe reference drug throughout the observation period, whereas the 2-azabicyclo[3.2.1]octane-derived counterpart retained only part ofthe reference activity.",
  "abstract_shown": true,
  "affiliations": [
    "Enamine Ltd., Winston Churchill Street 78, Kyїv, Ukraine, 02094",
    "Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyїv, Ukraine, 01601",
    "Enamine Scientific Research Institute, Winston Churchill Street 67, Kyїv, Ukraine, 02094",
    "Bienta/Enamine Ltd., Winston Churchill Street 78, Kyїv, 02094",
    "Institute of Organic Chemistry, NAS of Ukraine, Akademik Kukhar Street 5, Kyїv, Ukraine, 02066",
    "V. P. Kukhar Institute of Bioorganic Chemistry & Petrochemistry, NAS of Ukraine, Akademik Kukhar Street 1, Kyїv, 02066"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Maksym V. Leonenko"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Ihor M. Fesun"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Illia O. Doroshenko"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Mykhailo I. Adamovskyi"
    },
    {
      "affs": [
        3
      ],
      "name": "Iryna Pishel"
    },
    {
      "affs": [
        3
      ],
      "name": "Serhii Martseniuk"
    },
    {
      "affs": [
        3
      ],
      "name": "Vitalii Pyshnenko"
    },
    {
      "affs": [
        4
      ],
      "name": "Svetlana V. Shishkina"
    },
    {
      "affs": [
        3,
        5
      ],
      "name": "Petro Borysko"
    },
    {
      "affs": [
        1
      ],
      "name": "Vasyl G. Pivovarenko"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Bohdan V. Vashchenko"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Oleksandr O. Grygorenko",
      "orcid": "0000-0002-6036-5859"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/810cz103tn6qv.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15008681/v1",
  "fulltext_url": null,
  "id": "810cz103tn6qv",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008681/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|Cyclopropane Reaction Mechanisms"
    ]
  ],
  "openalex": "W7212292924",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15008681/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-10",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/810cz103tn6qv.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:19Z",
      "native_id": "10.26434/chemrxiv.15008681",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008681/v1"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1605|Cyclopropane Reaction Mechanisms",
      "subfield": "organic"
    }
  ],
  "title": "2-Azabicyclo[3.n.1]alkanes as Piperidine Bioisosteres",
  "title_text": "2-Azabicyclo[3.n.1]alkanes as Piperidine Bioisosteres",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:19Z",
  "url": "https://research.draconitic.com/paper/810cz103tn6qv",
  "venue": "ChemRxiv",
  "versions": []
}