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

• Published in: European journal of medicinal chemistry 2017-10, Vol.139, p.612-632
• Main Authors: Palanimuthu, Duraippandi, Poon, Rachal, Sahni, Sumit, Anjum, Rukhsana, Hibbs, David, Lin, Hsuan-Yu, Bernhardt, Paul V., Kalinowski, Danuta S., Richardson, Des R.
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Alzheimer Disease - drug therapy; Alzheimer's disease; Autophagy; Cell Proliferation - drug effects; Cell Survival - drug effects; Crystallography, X-Ray; Dose-Response Relationship, Drug; Humans; Hydrogen Peroxide - antagonists & inhibitors; Hydrogen Peroxide - pharmacology; Iron chelator; Models, Molecular; Molecular Structure; Oxidative stress; Structure-Activity Relationship; Thiosemicarbazone; Thiosemicarbazones - chemical synthesis; Thiosemicarbazones - chemistry; Thiosemicarbazones - pharmacology; Tumor Cells, Cultured
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.08.021

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. [Display omitted] •New multi-functional thiosemicarbazones were designed for Alzheimer's disease (AD).•The lead agent was pyridoxal 4-N-(1-benzylpiperidin-4-yl)thiosemicarbazone (PBPT).•PBPT showed substantial iron chelation efficacy and increased autophagic induction.•PBPT inhibited copper-mediated Aβ aggregation and acetylcholinesterase activity.•These properties show the potential of PBPT as a multi-functional AD therapeutic.