2. Academic Validation
  3. 1-Azaspiro[3.3]heptane as a Bioisostere of Piperidine

1-Azaspiro[3.3]heptane as a Bioisostere of Piperidine

  • Angew Chem Int Ed Engl. 2023 Dec 18;62(51):e202311583. doi: 10.1002/anie.202311583.
Alexander A Kirichok 1 2,  Hennadii Tkachuk 1,  Yevhenii Kozyriev 1 3,  Oleh Shablykin 1 4,  Oleksandr Datsenko 1,  Dmitry Granat 1,  Tetyana Yegorova 2,  Yuliya P Bas 2,  Vitalii Semirenko 1,  Iryna Pishel 1,  Vladimir Kubyshkin 1,  Dmytro Lesyk 5,  Oleksii Klymenko-Ulianov 5,  Pavel K Mykhailiuk 1 2
Affiliations

Affiliations

  • 1 Enamine Ltd, Winston Churchill Str. 78, 02094, Kyiv, Ukraine.
  • 2 Taras Shevchenko National University of Kyiv, Faculty of Chemistry, Volodymyrska 60, 01601, Kyiv, Ukraine.
  • 3 Oles Honchar Dnipro National University, Faculty of Chemistry, 72 Gagarina Ave., 49010, Dnipro, Ukraine.
  • 4 V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Akademika Kukharya 1, 02094, Kyiv, Ukraine.
  • 5 Bienta, Winston Churchill Str. 78, 02094, Kyiv, Ukraine.
PMID: 37819253 DOI: 10.1002/anie.202311583
Abstract

1-Azaspiro[3.3]heptanes were synthesized, characterized, and validated biologically as bioisosteres of piperidine. The key synthesis step was thermal [2+2] cycloaddition between endocyclic alkenes and the Graf isocyanate, ClO2 S-NCO, to give spirocyclic β-lactams. Reduction of the β-lactam ring with alane produced 1-azaspiro[3.3]heptanes. Incorporation of this core into the anesthetic drug bupivacaine instead of the piperidine fragment resulted in a new patent-free analogue with high activity.

Keywords

1-Azaspiro[3.3]Heptane; Bioisosteres; Drug Design; Medicinal Chemistry; Piperidine.

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