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Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease
Ist Teil von
European journal of medicinal chemistry, 2019-04, Vol.168, p.491-514
Ort / Verlag
France: Elsevier Masson SAS
Erscheinungsjahr
2019
Link zum Volltext
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
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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•Tacrine-tryptophan hybrids inhibited both cholinesterases in nanomolar concentrations.•Highlighted compound S-K1035 displayed Aβ42 self-aggregation as well as hAChE-induced Aβ40 aggregation.•Complex of TcAChE and S-K1035 was elucidated by X-ray crystallography.•Difference in activity between K1035 enantiomers was explored by conducting X-ray crystallography with hBChE.•In vivo pro-cognitive effect of S-K1035 was confirmed in scopolamine-induced amnesia model in rats.