Discovery of huperzine A-tacrine hybrids as potent inhibitors of human cholinesterases targeting their midgorge recognition sites

  • J Med Chem. 2006 Jun 1;49(11):3421-5. doi: 10.1021/jm060257t.
Sandra Gemma  1 ,  Emanuele Gabellieri ,  Paul Huleatt ,  Caterina Fattorusso ,  Marianna Borriello ,  Bruno Catalanotti ,  Stefania Butini ,  Meri De Angelis ,  Ettore Novellino ,  Vito Nacci ,  Tatyana Belinskaya ,  Ashima Saxena ,  Giuseppe Campiani
Affiliations
  • 1. Dipartimento Farmaco Chimico Tecnologico, Via Aldo Moro, Universita' di Siena, 53100 Siena, Italy.
PMID: 16722663 DOI: 10.1021/jm060257t
Abstract

We describe herein the development of novel huperzine A-tacrine hybrids characterized by 3-methylbicyclo[3.3.1]non-3-ene scaffolds. These compounds were specifically designed to establish tight interactions, through different binding modes, with the midgorge recognition sites of human acetylcholinesterase (hAChE: Y72, D74) and human butyrylcholinesterase (hBuChE: N68, D70) and their catalytic or peripheral sites. Compounds 5a-c show a markedly improved biological profile relative to tacrine and huperzine A.

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