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PreprintCC BYChemRxiv

2-Azabicyclo[3.n.1]alkanes as Piperidine Bioisosteres

  • Maksym V. Leonenko1
  • Ihor M. Fesun1,2
  • Illia O. Doroshenko2,3
  • Mykhailo I. Adamovskyi1,2
  • Iryna Pishel4
  • Serhii Martseniuk4
  • Vitalii Pyshnenko4
  • Svetlana V. Shishkina5
  • Petro Borysko4,6
  • Vasyl G. Pivovarenko2
  • Bohdan V. Vashchenko2,3
  • Oleksandr O. Grygorenko1,2,3
6 affiliations
  1. 1Enamine Ltd., Winston Churchill Street 78, Kyїv, Ukraine, 02094
  2. 2Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyїv, Ukraine, 01601
  3. 3Enamine Scientific Research Institute, Winston Churchill Street 67, Kyїv, Ukraine, 02094
  4. 4Bienta/Enamine Ltd., Winston Churchill Street 78, Kyїv, 02094
  5. 5Institute of Organic Chemistry, NAS of Ukraine, Akademik Kukhar Street 5, Kyїv, Ukraine, 02066
  6. 6V. P. Kukhar Institute of Bioorganic Chemistry & Petrochemistry, NAS of Ukraine, Akademik Kukhar Street 1, Kyїv, 02066
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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.

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Cite

BibTeXRIS
BibTeX
@misc{leonenko20262azabicyclo3n1alkanes,
  title = {{2-Azabicyclo[3.n.1]alkanes as Piperidine Bioisosteres}},
  author = {Maksym V. Leonenko and Ihor M. Fesun and Illia O. Doroshenko and Mykhailo I. Adamovskyi and Iryna Pishel and Serhii Martseniuk and Vitalii Pyshnenko and Svetlana V. Shishkina and Petro Borysko and Vasyl G. Pivovarenko and Bohdan V. Vashchenko and Oleksandr O. Grygorenko},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.15008681/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008681/v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - 2-Azabicyclo[3.n.1]alkanes as Piperidine Bioisosteres
AU  - Maksym V. Leonenko
AU  - Ihor M. Fesun
AU  - Illia O. Doroshenko
AU  - Mykhailo I. Adamovskyi
AU  - Iryna Pishel
AU  - Serhii Martseniuk
AU  - Vitalii Pyshnenko
AU  - Svetlana V. Shishkina
AU  - Petro Borysko
AU  - Vasyl G. Pivovarenko
AU  - Bohdan V. Vashchenko
AU  - Oleksandr O. Grygorenko
PY  - 2026
DA  - 2026/09/10
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15008681/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008681/v1
AB  - 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.
ER  -