title: Discovery of huperzine A-tacrine hybrids as potent inhibitors of human cholinesterases targeting their midgorge recognition sites.
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.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Via Aldo Moro, Universita' di Siena, 53100 Siena, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.forename: Emanuele
authors.initials: E
authors.lastname: Gabellieri
authors.forename: Paul
authors.initials: P
authors.lastname: Huleatt
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
authors.forename: Marianna
authors.initials: M
authors.lastname: Borriello
authors.forename: Bruno
authors.initials: B
authors.lastname: Catalanotti
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Meri
authors.initials: M
authors.lastname: De Angelis
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Vito
authors.initials: V
authors.lastname: Nacci
authors.forename: Tatyana
authors.initials: T
authors.lastname: Belinskaya
authors.forename: Ashima
authors.initials: A
authors.lastname: Saxena
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000470:Alkaloids; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry*; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D012717:Sesquiterpenes; C050426:huperzine A; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase