Tacrine-Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity.
Coupling of two distinct pharmacophores, tacrine and trolox, endowed with different biological properties, afforded 21 hybrid compounds as novel multifunctional candidates against Alzheimer's disease. Several of them showed improved inhibitory properties toward acetylcholinesterase (AChE) in relation to tacrine. These hybrids also scavenged free radicals. Molecular modeling studies in tandem with kinetic analysis exhibited that these hybrids target both catalytic active site as well as peripheral anionic site of AChE. In addition, incorporation of the moiety bearing antioxidant abilities displayed negligible toxicity on human hepatic cells. This striking effect was explained by formation of nontoxic metabolites after 1 h incubation in human liver microsomes system. Finally, tacrine-trolox hybrids exhibited low in vivo toxicity after im administration in rats and potential to penetrate across blood-brain barrier. All of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7u as the lead structure worthy of further investigation.
Biomedical Research Centre, University Hospital Hradec Kralove , Sokolska 581, 500 05 Hradec Kralove, Czech Republic.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence , Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.|Department of Intensive Medicine and Forensic Studies; Department of Physiology and Pathophysiology, Faculty of Medicine, University of Ostrava , Syllabova 19, 703 00 Ostrava, Czech Republic.
Eugenie
E
Nepovimova
Biomedical Research Centre, University Hospital Hradec Kralove , Sokolska 581, 500 05 Hradec Kralove, Czech Republic.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence , Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.|National Institute of Mental Health , Topolova 748, 250 67 Klecany, Czech Republic.
Jan
J
Korabecny
Biomedical Research Centre, University Hospital Hradec Kralove , Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
Rafael
R
Dolezal
Biomedical Research Centre, University Hospital Hradec Kralove , Sokolska 581, 500 05 Hradec Kralove, Czech Republic.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence , Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
Katerina
K
Babkova
Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague , Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
Ales
A
Ondrejicek
Biomedical Research Centre, University Hospital Hradec Kralove , Sokolska 581, 500 05 Hradec Kralove, Czech Republic.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence , Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
Daniel
D
Jun
Biomedical Research Centre, University Hospital Hradec Kralove , Sokolska 581, 500 05 Hradec Kralove, Czech Republic.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence , Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
Vendula
V
Sepsova
Biomedical Research Centre, University Hospital Hradec Kralove , Sokolska 581, 500 05 Hradec Kralove, Czech Republic.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence , Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
Anna
A
Horova
Biomedical Research Centre, University Hospital Hradec Kralove , Sokolska 581, 500 05 Hradec Kralove, Czech Republic.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence , Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
Martina
M
Hrabinova
Biomedical Research Centre, University Hospital Hradec Kralove , Sokolska 581, 500 05 Hradec Kralove, Czech Republic.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence , Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.|National Institute of Mental Health , Topolova 748, 250 67 Klecany, Czech Republic.
Ondrej
O
Soukup
Biomedical Research Centre, University Hospital Hradec Kralove , Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
Neslihan
N
Bukum
Biomedical Research Centre, University Hospital Hradec Kralove , Sokolska 581, 500 05 Hradec Kralove, Czech Republic.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence , Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
Petr
P
Jost
Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence , Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
Lubica
L
Muckova
Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence , Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
Jiri
J
Kassa
Biomedical Research Centre, University Hospital Hradec Kralove , Sokolska 581, 500 05 Hradec Kralove, Czech Republic.|Department of Intensive Medicine and Forensic Studies; Department of Physiology and Pathophysiology, Faculty of Medicine, University of Ostrava , Syllabova 19, 703 00 Ostrava, Czech Republic.
David
D
Malinak
Biomedical Research Centre, University Hospital Hradec Kralove , Sokolska 581, 500 05 Hradec Kralove, Czech Republic.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence , Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
Martin
M
Andrs
Biomedical Research Centre, University Hospital Hradec Kralove , Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
Kamil
K
Kuca
D000110:Acetylcholinesterase / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D001812:Blood-Brain Barrier; D002384:Catalysis; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002839:Chromans / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D015195:Drug Design; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007273:Injections, Intramuscular; D007700:Kinetics; D008024:Ligands; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D051381:Rats; D017208:Rats, Wistar; D013619:Tacrine / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity
D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D002839:Chromans; D016166:Free Radical Scavengers; D008024:Ligands; D013619:Tacrine; D000110:Acetylcholinesterase; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid