Discovery of a NADPH oxidase inhibitor, (E)-3-cyclohexyl-5-(4-((2-hydroxyethyl)(methyl)amino)benzylidene)-1-methyl-2-thioxoimidazolidin-4-oneone, as a novel therapeutic for Parkinson's disease

Seunghwan Shim, Da Un Jeong, Hyemi Kim, Chae Yun Kim, Hyejun Park, Yinglan Jin, Kyung Min Kim, Hwa Jeong Lee, Dong Hwan Kim, Yun Soo Bae, Yongseok Choi

Research output: Contribution to journalArticlepeer-review

Abstract

Several lines of evidence indicated that generation of NADPH oxidase (Nox)-mediated reactive oxygen species are associated with neuronal inflammation, leading to Parkinson's disease (PD). Novel benzylidene-1-methyl-2-thioxoimidazolidin-one derivatives as Nox inhibitors were designed and synthesized in order to increase blood-brain barrier (BBB) permeability to target Nox in brain cells. In lucigenin chemiluminescence assay, eight compounds showed excellent inhibition activity against NADPH oxidases and parallel artificial membrane permeability assay (PAMPA) identified compound 11 with high passive permeability. To validate the effect of compound 11 on neuronal inflammation, we tested the regulatory activity of compound 11 in lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokines in BV-2 microglial cells and LPS-mediated microglial migration. Treatment of BV2 cells with compound 11 resulted in suppressed production of pro-inflammatory cytokines and migration activity of BV2 cells in response to LPS. To evaluate the therapeutic efficacy of compound 11 in PD animal model, compound 11 was applied to MPTP-induced PD mouse model. Oral administration of compound 11 (30 mg/kg/daily, 4 weeks) into the mice resulted in suppression of dopaminergic neuronal death in substantia nigra (SN) and in striatum as well as inhibition of microglial migration into SN. These results implicate compound 11 as a novel therapeutic agent for the treatment of PD.

Original languageEnglish
Article number114854
JournalEuropean Journal of Medicinal Chemistry
Volume244
DOIs
Publication statusPublished - 2022 Dec 15

Keywords

  • Blood-brain barrier (BBB) permeability
  • MPTP-Induced PD mouse Model
  • NADPH Oxidase (Nox)
  • Nox inhibitor
  • Parkinson's disease
  • Reactive oxygen species (ROS)

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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