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

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 synthes...

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Published in:European journal of medicinal chemistry 2022-12, Vol.244, p.114854-114854, Article 114854
Main Authors: Shim, Seunghwan, Jeong, Da Un, Kim, Hyemi, Kim, Chae Yun, Park, Hyejun, Jin, Yinglan, Kim, Kyung Min, Lee, Hwa Jeong, Kim, Dong Hwan, Bae, Yun Soo, Choi, Yongseok
Format: Article
Language:English
Subjects:
Blood-brain barrier (BBB) permeability
MPTP-Induced PD mouse Model
NADPH Oxidase (Nox)
Nox inhibitor
Parkinson's disease
Reactive oxygen species (ROS)
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Summary: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. [Display omitted] •ROS overproduction by NOX plays a key role in neuronal damage critical in Parkinson's disease.•Benzylidene-1-methyl-2-thioxoimidazolidinone derivatives showed potent inhibitory activities against NADPH oxidases.•Compound 11 could cross BBB and suppressed production of pro-inflammatory cytokines and migration activity of BV2 cells in response to LPS.•Compound 11 showed a good therapeutic efficacy in MPTP-induced Parkinson's disease animal model.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2022.114854