New thiourea and benzamide derivatives of 2-aminothiazole as multi-target agents against Alzheimer's disease: Design, synthesis, and biological evaluation

Bioorg Chem. 2023 Feb:131:106322. doi: 10.1016/j.bioorg.2022.106322. Epub 2022 Dec 14.

Abstract

In this study, two series of compounds were designed and synthesized, bearing thiourea and benzamide derivatives at position 2 of 4-subtituted-2-aminothiazole, respectively. Then, the inhibition potency of all final compounds for cholinesterase enzymes were evaluated. Among the thiourea derivatives, 3c (IC50 = 0.33 μM) was identified as the most potent and selective butyrylcholinesterase inhibitor. Additionally, benzamide derivative 10e (AChE IC50 = 1.47 and BChE IC50 = 11.40 μM) was found as a dual cholinesterase inhibitor. The type of inhibition for both compounds was determined by kinetic studies and the results showed that the compounds were mixed type inhibitors. Moreover, all title compounds were investigated in terms of their antioxidant (DPHH, ORAC) and metal chelator activities. In addition, the neuroprotective effects of selected compounds (3c, 3e, 6c, 6e and 10e) against H2O2-induced damage in the PC12 cell line were tested. The experimental findings demonstrated that thiourea-derived 6e (40.4 %) and benzamide-derived 10e (37.8 %) have a neuroprotective effect of about half as ferulic acid at 10 μM. Subsequently, the cytotoxicity of selected compounds was examined by the MTT assay, and the compounds were found not to have cytotoxic effect on the PC12 cell line in 24 h. Additionally, compounds 6e and 10e were also found to be more effective in inhibiting the release of IL-1β, IL-6, TNF-α and NO compared to other selected compounds in this study.

Keywords: 2-aminothiazole; Alzheimer’s disease; Anti-inflammatory; Antioxidant; Cholinesterase inhibitory activity; Metal-chelating; Molecular docking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease* / drug therapy
  • Benzamides* / chemistry
  • Benzamides* / pharmacology
  • Butyrylcholinesterase / metabolism
  • Cholinesterase Inhibitors* / chemistry
  • Cholinesterase Inhibitors* / pharmacology
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Kinetics
  • Molecular Docking Simulation
  • Neuroprotective Agents* / chemistry
  • Neuroprotective Agents* / pharmacology
  • Structure-Activity Relationship
  • Thiourea* / analogs & derivatives
  • Thiourea* / pharmacology

Substances

  • 2-aminothiazole
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Cholinesterase Inhibitors
  • Hydrogen Peroxide
  • Neuroprotective Agents
  • Thiourea
  • Benzamides