2. Academic Validation
  3. Tacrine-Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity

Tacrine-Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity

  • J Med Chem. 2015 Nov 25;58(22):8985-9003. doi: 10.1021/acs.jmedchem.5b01325.
Eugenie Nepovimova 1 2 3,  Jan Korabecny 1 2 4,  Rafael Dolezal 1,  Katerina Babkova 1 2,  Ales Ondrejicek 5,  Daniel Jun 1 2,  Vendula Sepsova 1 2,  Anna Horova 1 2,  Martina Hrabinova 1 2,  Ondrej Soukup 1 2 4,  Neslihan Bukum 1,  Petr Jost 1 2,  Lubica Muckova 2,  Jiri Kassa 2,  David Malinak 1 3,  Martin Andrs 1 2,  Kamil Kuca 1
Affiliations

Affiliations

  • 1 Biomedical Research Centre, University Hospital Hradec Kralove , Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
  • 2 Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence , Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
  • 3 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.
  • 4 National Institute of Mental Health , Topolova 748, 250 67 Klecany, Czech Republic.
  • 5 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.
PMID: 26503905 DOI: 10.1021/acs.jmedchem.5b01325
Abstract

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.

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