A novel class of thiosemicarbazones show multi-functional activity for the treatment of Alzheimer%26apos;s disease

作者：Palanimuthu Duraippandi; Poon Rachal; Sahni Sumit; Anjum Rukhsana; Hibbs David; Lin Hsuan Yu; Bernhardt Paul V; Kalinowski Danuta S; Richardson Des R

来源：European Journal of Medicinal Chemistry, 2017, 139: 612-632.

DOI：10.1016/j.ejmech.2017.08.021

• Alzheimer's disease
• Acetylcholinesterase
• Thiosemicarbazone
• Iron chelator
• Oxidative stress
• Autophagy

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-p 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.

• 出版日期2017-10-20