Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease.

Autor: Chalupova K; National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic; Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic., Korabecny J; National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic., Bartolini M; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, I-40126, Bologna, Italy., Monti B; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, I-40126, Bologna, Italy., Lamba D; Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Area Science Park - Basovizza, S.S. n° 14-Km 163.5, I-34149, Trieste, Italy., Caliandro R; Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Area Science Park - Basovizza, S.S. n° 14-Km 163.5, I-34149, Trieste, Italy., Pesaresi A; Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Area Science Park - Basovizza, S.S. n° 14-Km 163.5, I-34149, Trieste, Italy., Brazzolotto X; Institut de Recherche Biomédicale des Armées, Département de Toxicologie et Risques Chimiques, 1 Place Général Valérie André, 91220, Brétigny-sur-Orge, France., Gastellier AJ; Institut de Recherche Biomédicale des Armées, Département de Toxicologie et Risques Chimiques, 1 Place Général Valérie André, 91220, Brétigny-sur-Orge, France., Nachon F; Institut de Recherche Biomédicale des Armées, Département de Toxicologie et Risques Chimiques, 1 Place Général Valérie André, 91220, Brétigny-sur-Orge, France., Pejchal J; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic., Jarosova M; 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., Hepnarova V; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic., Jun D; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic., Hrabinova M; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic., Dolezal R; Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic., Zdarova Karasova J; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic., Mzik M; Institute of Clinical Biochemistry and Diagnosis, University Hospital, Sokolska 581, 500 05, Hradec Kralove, Czech Republic., Kristofikova Z; National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic., Misik J; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic., Muckova L; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic., Jost P; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic., Soukup O; National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic., Benkova M; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic., Setnicka V; Department of Analytical Chemistry, University of Chemistry and Technology Prague, Technicka 5, 166 28, Prague, Czech Republic., Habartova L; Department of Analytical Chemistry, University of Chemistry and Technology Prague, Technicka 5, 166 28, Prague, Czech Republic., Chvojkova M; National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic; Institute of Physiology, Czech Academy of Sciences, Videnska 1083, 142 20, Prague, Czech Republic., Kleteckova L; National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic; Institute of Physiology, Czech Academy of Sciences, Videnska 1083, 142 20, Prague, Czech Republic., Vales K; National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic; Institute of Physiology, Czech Academy of Sciences, Videnska 1083, 142 20, Prague, Czech Republic., Mezeiova E; National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic., Uliassi E; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, I-40126, Bologna, Italy., Valis M; Department of Neurology, Charles University in Prague, Faculty of Medicine in Hradec Kralove and University Hospital, Simkova 870, 500 03, Hradec Kralove, Czech Republic., Nepovimova E; Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic., Bolognesi ML; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, I-40126, Bologna, Italy. Electronic address: marialaura.bolognesi@unibo.it., Kuca K; Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic. Electronic address: kamil.kuca@fnhk.cz.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2019 Apr 15; Vol. 168, pp. 491-514. Date of Electronic Publication: 2019 Feb 27.
DOI: 10.1016/j.ejmech.2019.02.021
Abstrakt: 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 IC 50 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 Aβ 42 self-aggregation (58.6 ± 5.1% at 50 μM) as well as hAChE-induced Aβ 40 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.
(Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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