2. Academic Validation
  3. Multi-target potential of newly designed tacrine-derived cholinesterase inhibitors: Synthesis, computational and pharmacological study

Multi-target potential of newly designed tacrine-derived cholinesterase inhibitors: Synthesis, computational and pharmacological study

  • Bioorg Med Chem. 2024 Mar 1:101:117649. doi: 10.1016/j.bmc.2024.117649.
Ivana I Jevtić 1,  Relja V Suručić 2,  Gordana Tovilović-Kovačević 3,  Nevena Zogović 4,  Slađana V Kostić-Rajačić 5,  Deana B Andrić 6,  Jelena Z Penjišević 7
Affiliations

Affiliations

  • 1 University of Belgrade-Institute of Chemistry, Technology and Metallurgy, Department of Chemistry, Njegoševa 12, 11000 Belgrade, Serbia. Electronic address: [email protected].
  • 2 University of Banja Luka, Faculty of Medicine, Save Mrkalja 14, 78000 Banja Luka, Bosnia and Herzegovina. Electronic address: [email protected].
  • 3 University of Belgrade-Institute for Biological Research "Siniša Stanković"-National Institute of the Republic of Serbia, Bulevar despota Stefana 142, 11108 Belgrade, Serbia. Electronic address: [email protected].
  • 4 University of Belgrade-Institute for Biological Research "Siniša Stanković"-National Institute of the Republic of Serbia, Bulevar despota Stefana 142, 11108 Belgrade, Serbia. Electronic address: [email protected].
  • 5 University of Belgrade-Institute of Chemistry, Technology and Metallurgy, Department of Chemistry, Njegoševa 12, 11000 Belgrade, Serbia. Electronic address: [email protected].
  • 6 University of Belgrade, Faculty of Chemistry, Department of Organic chemistry, Studentski trg 12-16, 11158 Belgrade, Serbia. Electronic address: [email protected].
  • 7 University of Belgrade-Institute of Chemistry, Technology and Metallurgy, Department of Chemistry, Njegoševa 12, 11000 Belgrade, Serbia. Electronic address: [email protected].
PMID: 38401458 DOI: 10.1016/j.bmc.2024.117649
Abstract

Simple and scalable synthetic approach was used for the preparation of thirteen novel tacrine derivatives consisting of tacrine and N-aryl-piperidine-4-carboxamide moiety connected by a five-methylene group linker. An anti-Alzheimer disease (AD) potential of newly designed tacrine derivatives was evaluated against two important AD targets, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). In vitro pharmacological evaluation showed strong ChE inhibitory activity of all compounds, with IC50 values ranging from 117.5 to 455 nM for AChE and 34 to 324 nM for BuChE. As a representative of the series with the best cytotoxicity / ChE inhibitory activity ratio, expressed as the selectivity index (SI), 2-chlorobenzoyl derivative demonstrated mixed-type inhibition on AChE and BuChE, suggesting binding to both CAS and PAS of the Enzymes. It also exhibited antioxidant capacity and neuroprotective potential against Amyloid-β (Aβ) toxicity in the culture of neuron-like cells. In-depth computational analysis corroborated well with in vitro ChE inhibition, illuminating that all compounds exhibit significant potential in targeting both Enzymes. Molecular dynamics (MD) simulations revealed that 2-chlorobenzoyl derivative, created complexes with AChE and BuChE that demonstrated sufficient stability throughout the observed MD simulation. Computationally predicted ADME properties indicated that these compounds should have good blood-brain barrier (BBB) permeability, an important factor for CNS-targeting drugs. Overall, all tested compounds showed promising pharmacological behavior, highlighting the multi-target potential of 2-chlorobenzoyl derivative which should be further investigated as a new lead in the drug development process.

Keywords

ADME; Alzheimer’s disease; Cholinesterase; Cytotoxicity; Molecular docking; Molecular dynamics; Neuroprotection; Piperidine-4-carboxamide; Tacrine.

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