Discovery of huperzine A-tacrine hybrids as potent inhibitors of human cholinesterases targeting their midgorge recognition sites.
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.
Gemma
Sandra
S
Dipartimento Farmaco Chimico Tecnologico, Via Aldo Moro, Universita' di Siena, 53100 Siena, Italy.
Gabellieri
Emanuele
E
Huleatt
Paul
P
Fattorusso
Caterina
C
Borriello
Marianna
M
Catalanotti
Bruno
B
Butini
Stefania
S
De Angelis
Meri
M
Novellino
Ettore
E
Nacci
Vito
V
Belinskaya
Tatyana
T
Saxena
Ashima
A
Campiani
Giuseppe
G
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
D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D012717:Sesquiterpenes; C050426:huperzine A; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase