2. Academic Validation
  3. Thioxanthenone-based derivatives as multitarget therapeutic leads for Alzheimer's disease

Thioxanthenone-based derivatives as multitarget therapeutic leads for Alzheimer's disease

  • Eur J Med Chem. 2023 Mar 15;250:115169. doi: 10.1016/j.ejmech.2023.115169.
Michele Tonelli 1,  Marco Catto 2,  Raimon Sabaté 3,  Valeria Francesconi 4,  Erik Laurini 5,  Sabrina Pricl 6,  Leonardo Pisani 7,  Daniela Valeria Miniero 8,  Grazia Maria Liuzzi 8,  Elena Gatta 9,  Annalisa Relini 9,  Rosalina Gavín 10,  Jose Antonio Del Rio 10,  Fabio Sparatore 4,  Angelo Carotti 7
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Genoa, 16132, Genoa, Italy. Electronic address: [email protected].
  • 2 Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, 70125, Bari, Italy. Electronic address: [email protected].
  • 3 Department of Pharmacy and Pharmaceutical Technology and Physical-Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, 08028, Barcelona, Spain. Electronic address: [email protected].
  • 4 Department of Pharmacy, University of Genoa, 16132, Genoa, Italy.
  • 5 Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), Department of Engineering and Architecture, University of Trieste, 34127, Trieste, Italy.
  • 6 Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), Department of Engineering and Architecture, University of Trieste, 34127, Trieste, Italy; Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236, Lodz, Poland.
  • 7 Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, 70125, Bari, Italy.
  • 8 Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70125, Bari, Italy.
  • 9 Department of Physics, University of Genoa, 16146, Genoa, Italy.
  • 10 Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, 08028, Barcelona, Spain; Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, 08028, Barcelona, Spain; Institute of Neuroscience, University of Barcelona, 08028, Barcelona, Spain.
PMID: 36753881 DOI: 10.1016/j.ejmech.2023.115169
Abstract

A set of twenty-five thioxanthene-9-one and xanthene-9-one derivatives, that were previously shown to inhibit cholinesterases (ChEs) and amyloid β (Aβ40) aggregation, were evaluated for the inhibition of Tau Protein aggregation. All compounds exhibited a good activity, and eight of them (5-8, 10, 14, 15 and 20) shared comparable low micromolar inhibitory potency versus Aβ40 aggregation and human acetylcholinesterase (AChE), while inhibiting human butyrylcholinesterase (BChE) even at submicromolar concentration. Compound 20 showed outstanding biological data, inhibiting Tau Protein and Aβ40 aggregation with IC50 = 1.8 and 1.3 μM, respectively. Moreover, at 0.1-10 μM it also exhibited neuroprotective activity against tau toxicity induced by okadoic acid in human neuroblastoma SH-SY5Y cells, that was comparable to that of estradiol and PD38. In preliminary toxicity studies, these interesting results for compound 20 are somewhat conflicting with a narrow safety window. However, compound 10, although endowed with a little lower potency for tau and Aβ aggregation inhibition additionally demonstrated good inhibition of ChEs and rather low cytotoxicity. Compound 4 is also worth of note for its high potency as hBChE inhibitor (IC50 = 7 nM) and for the three order of magnitude selectivity versus hAChE. Molecular modelling studies were performed to explain the different behavior of compounds 4 and 20 towards hBChE. The observed balance of the inhibitory potencies versus the relevant targets indicates the thioxanthene-9-one derivatives as potential MTDLs for AD therapy, provided that the safety window will be improved by further structural variations, currently under investigation.

Keywords

AChE and BChE inhibition; Alzheimer's disease; Aβ and tau aggregation inhibition; Multitarget-directed ligands (MTDLs); Thioxanthene-9-one and xanthen-9-one derivatives.

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