Tacrine - Benzothiazoles: Novel class of potential multitarget anti-Alzheimeŕs drugs dealing with cholinergic, amyloid and mitochondrial systems

Bioorg Chem. 2021 Feb:107:104596. doi: 10.1016/j.bioorg.2020.104596. Epub 2020 Dec 28.

Abstract

A series of tacrine - benzothiazole hybrids incorporate inhibitors of acetylcholinesterase (AChE), amyloid β (Aβ) aggregation and mitochondrial enzyme ABAD, whose interaction with Aβ leads to mitochondrial dysfunction, into a single molecule. In vitro, several of 25 final compounds exerted excellent anti-AChE properties and interesting capabilities to block Aβ aggregation. The best derivative of the series could be considered 10w that was found to be highly potent and selective towards AChE with the IC50 value in nanomolar range. Moreover, the same drug candidate exerted absolutely the best results of the series against ABAD, decreasing its activity by 23% at 100 µM concentration. Regarding the cytotoxicity profile of highlighted compound, it roughly matched that of its parent compound - 6-chlorotacrine. Finally, 10w was forwarded for in vivo scopolamine-induced amnesia experiment consisting of Morris Water Maze test, where it demonstrated mild procognitive effect. Taking into account all in vitro and in vivo data, highlighted derivative 10w could be considered as the lead structure worthy of further investigation.

Keywords: ABAD; Acetylcholinesterase Inhibitors; Alzheimer’s disease; Amyloid β; Benzothiazole; MTDLs; Tacrine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxyacyl CoA Dehydrogenases / antagonists & inhibitors
  • 3-Hydroxyacyl CoA Dehydrogenases / metabolism
  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Benzothiazoles / chemistry
  • Benzothiazoles / pharmacology*
  • Cholinergic Agents / chemical synthesis
  • Cholinergic Agents / chemistry
  • Cholinergic Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Protein Aggregates / drug effects
  • Structure-Activity Relationship
  • Tacrine / chemistry
  • Tacrine / pharmacology*

Substances

  • Amyloid beta-Peptides
  • Benzothiazoles
  • Cholinergic Agents
  • Enzyme Inhibitors
  • Neuroprotective Agents
  • Protein Aggregates
  • Tacrine
  • 3-Hydroxyacyl CoA Dehydrogenases
  • HSD17B10 protein, human
  • Acetylcholinesterase