2. Academic Validation
  3. A novel class of thiosemicarbazones show multi-functional activity for the treatment of Alzheimer's disease

A novel class of thiosemicarbazones show multi-functional activity for the treatment of Alzheimer's disease

  • Eur J Med Chem. 2017 Oct 20:139:612-632. doi: 10.1016/j.ejmech.2017.08.021.
Duraippandi Palanimuthu 1,  Rachal Poon 1,  Sumit Sahni 1,  Rukhsana Anjum 1,  David Hibbs 2,  Hsuan-Yu Lin 2,  Paul V Bernhardt 3,  Danuta S Kalinowski 4,  Des R Richardson 5
Affiliations

Affiliations

  • 1 Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, New South Wales, 2006, Australia.
  • 2 Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, 2006, Australia.
  • 3 School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, 4072, Australia.
  • 4 Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, New South Wales, 2006, Australia. Electronic address: danuta.kalinowski@sydney.edu.au.
  • 5 Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, New South Wales, 2006, Australia. Electronic address: d.richardson@med.usyd.edu.au.
PMID: 28841514 DOI: 10.1016/j.ejmech.2017.08.021
Abstract

Over 44 million people live with Alzheimer's disease (AD) worldwide. Currently, only symptomatic treatments are available for AD and no cure exists. Considering the lack of effective treatments for AD due to its multi-factorial pathology, development of novel multi-target-directed drugs are desirable. Herein, we report the development of a novel series of thiosemicarbazones derived from 1-benzylpiperidine, a pharmacophore within the acetylcholinesterase inhibitor, Donepezil. These thiosemicarbazones were designed to target five major AD hallmarks, including: low acetylcholine levels, dysfunctional Autophagy, metal dys-homeostasis, protein aggregation and oxidative stress. Of these thiosemicarbazones, pyridoxal 4-N-(1-benzylpiperidin-4-yl)thiosemicarbazone (PBPT) emerged as the lead compound. This agent demonstrated the most promising multi-functional activity by exhibiting very low anti-proliferative activity, substantial iron chelation efficacy, inhibition of copper-mediated Amyloid-β aggregation, inhibition of oxidative stress, moderate acetylcholinesterase inhibitory activity and autophagic induction. These diverse properties highlight the potential of the lead ligand, PBPT, as a promising multi-functional agent for AD treatment.

Keywords

Acetylcholinesterase; Alzheimer's disease; Autophagy; Iron chelator; Oxidative stress; Thiosemicarbazone.

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