Synthesis and anticholinesterase activity of huperzine A analogues containing phenol and catechol replacements for the pyridone ring.
Based upon modeling results obtained using the crystal structure of huperzine A in complex with acetylcholinesterase (AChE), two novel analogues of this potent AChE inhibitor were designed with phenol or catechol rings replacing the pyridone ring. From the modeling studies, the catechol analogue appeared capable of replacing one of the crystallographic waters bridging huperzine with Tyr 130 and Glu 199 of AChE. The synthesis of these materials by use of a palladium catalyzed bicycloannulation strategy is detailed together with the results of AChE inhibition assays.
Campiani
G
G
Dipartimento Farmaco Chimico Tecnologico, Siena University, Italy.
Kozikowski
A P
AP
Wang
S
S
Ming
L
L
Nacci
V
V
Saxena
A
A
Doctor
B P
BP
D000470:Alkaloids; D000818:Animals; D002384:Catalysis; D002396:Catechols / Q000138:chemical synthesis / Q000494:pharmacology; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008958:Models, Molecular; D010165:Palladium; D010636:Phenols / Q000138:chemical synthesis / Q000494:pharmacology; D011728:Pyridones / Q000737:chemistry; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000470:Alkaloids; D002396:Catechols; D002800:Cholinesterase Inhibitors; D010636:Phenols; D011728:Pyridones; D012717:Sesquiterpenes; C050426:huperzine A; D010165:Palladium