European Journal of Medicinal Chemistry p. 491 - 514 (2019)
Update date:2022-08-30
Topics:
Chalupova, Katarina
Korabecny, Jan
Bartolini, Manuela
Monti, Barbara
Lamba, Doriano
Caliandro, Rosanna
Pesaresi, Alessandro
Brazzolotto, Xavier
Gastellier, Anne-Julie
Nachon, Florian
Pejchal, Jaroslav
Jarosova, Michaela
Hepnarova, Vendula
Jun, Daniel
Hrabinova, Martina
Dolezal, Rafael
Zdarova Karasova, Jana
Mzik, Martin
Kristofikova, Zdena
Misik, Jan
Muckova, Lubica
Jost, Petr
Soukup, Ondrej
Benkova, Marketa
Setnicka, Vladimir
Habartova, Lucie
Chvojkova, Marketa
Kleteckova, Lenka
Vales, Karel
Mezeiova, Eva
Uliassi, Elisa
Valis, Martin
Nepovimova, Eugenie
Bolognesi, Maria Laura
Kuca, Kamil
A combination of tacrine and tryptophan led to the development of a new family of heterodimers as multi-target agents with potential to treat Alzheimer's disease. Based on the in vitro biological profile, compound S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), demonstrating balanced IC50 values of 6.3 and 9.1 nM, respectively. For all the tacrine-tryptophan heterodimers, favorable inhibitory effect on hAChE as well as on hBChE was coined to the optimal spacer length ranging from five to eight carbon atoms between these two pharmacophores. S-K1035 also showed good ability to inhibit Aβ42 self-aggregation (58.6 ± 5.1% at 50 μM) as well as hAChE-induced Aβ40 aggregation (48.3 ± 6.3% at 100 μM). The X-ray crystallographic analysis of TcAChE in complex with S-K1035 pinpointed the utility of the hybridization strategy applied and the structures determined with the two K1035 enantiomers in complex with hBChE could explain the higher inhibition potency of S-K1035. Other in vitro evaluations predicted the ability of S-K1035 to cross blood-brain barrier and to exert a moderate inhibition potency against neuronal nitric oxide synthase. Based on the initial promising biochemical data and a safer in vivo toxicity compared to tacrine, S-K1035 was administered to scopolamine-treated rats being able to dose-dependently revert amnesia.
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