Synthesis and biological evaluation of NO-donor-tacrine hybrids as hepatoprotective anti-Alzheimer drug candidates.
In search of safer anti-Alzheimer drugs, 14 NO-donor-tacrine hybrids (1- 14) were synthesized and evaluated for their ability to inhibit cholinesterases and for vasorelaxation effects. Compounds 1- 13 showed good cholinesterases inhibitory activities in vitro, while 14, particularly, was highly selective, preferring butyrylcholinesterase rather than acetylcholinesterase. Four selected compounds (1, 9, 11, and 14) moderately relaxed the porcine pulmonary arteries in organ bath. In the hepatotoxicity study, significant hepatotoxicity was caused by tacrine but not by 9.
Fang
Lei
L
Appenroth
Dorothea
D
Decker
Michael
M
Kiehntopf
Michael
M
Roegler
Carolin
C
Deufel
Thomas
T
Fleck
Christian
C
Peng
Sixun
S
Zhang
Yihua
Y
Lehmann
Jochen
J
D000110:Acetylcholinesterase / Q000737:chemistry; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D009126:Muscle Relaxation; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D013552:Swine; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity
D002800:Cholinesterase Inhibitors; D020030:Nitric Oxide Donors; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase