Structure-Based Design, Synthesis, Biological Evaluation, and Molecular Docking of Novel PDE10 Inhibitors With Antioxidant Activities

Phosphodiesterase 10 is a promising target for the treatment of a series of central nervous system (CNS) diseases. Imbalance between oxidative stress and antioxidant defense systems as a universal condition in neurodegenerative disorders is widely studied as a potential therapy for CNS diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). To discover multifunctional pharmaceuticals as a treatment for neurodegenerative diseases, a series of quinazoline-based derivatives with PDE10 inhibitory activities and antioxidant activities were designed and synthesized. Nine out of 13 designed compounds showed good PDE10 inhibition at the concentration of 1.0 μM. Among these compounds, eight exhibited moderate to excellent antioxidant activity with ORAC (oxygen radical absorbance capacity) value above 1.0. Molecular docking was performed for better understanding of the binding patterns of these compounds with PDE10. Compound 11e, which showed remarkable inhibitory activity against PDE10 and antioxidant activity may serve as a lead for the further modification.

• Publication year

  2018

• Venue

  Frontiers in Chemistry

• Publication date

  2018-05-15

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.3389/fchem.2018.00167PMID 29868568PMCID 5962708
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders

  2017cited by this paper
• Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents.

  2016cited by this paper
• Phosphodiesterase 10A inhibitor, MP-10 (PF-2545920), produces greater induction of c-Fos in dopamine D2 neurons than in D1 neurons in the neostriatum.

  2015cited by this paper
• Pharmacological evaluation of a novel phosphodiesterase 10A inhibitor in models of antipsychotic activity and cognition.

  2015cited by this paper
• Oxidative Stress in Neurodegenerative Diseases

  2015cited by this paper
• In Vivo Pharmacological Characterization of TAK-063, a Potent and Selective Phosphodiesterase 10A Inhibitor with Antipsychotic-Like Activity in Rodents

  2015cited by this paper
• Molecular dynamics-based discovery of novel phosphodiesterase-9A inhibitors with non-pyrazolopyrimidinone scaffolds.

  2015cited by this paper
• The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents.

  2015cited by this paper
• The discovery and development of new potential antioxidant agents for the treatment of neurodegenerative diseases

  2014cited by this paper
• Phosphodiesterase 10A inhibitors: a 2009 – 2012 patent update

  2013cited by this paper
• Antioxidant clinical trials in mild cognitive impairment and Alzheimer's disease.

  2012cited by this paper
• Oxidative stress in neurodegenerative diseases

  2012cited by this paper
• Synthesis and structure-activity relationships of (aryloxy)quinazoline ureas as novel, potent, and selective vascular endothelial growth factor receptor-2 inhibitors.

  2012cited by this paper
• Use of structure-based design to discover a potent, selective, in vivo active phosphodiesterase 10A inhibitor lead series for the treatment of schizophrenia.

  2011cited by this paper
• Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions.

  2011cited by this paper
• Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown.

  2010cited by this paper
• Cross-linking of protein crystals as an aid in the generation of binary protein-ligand crystal complexes, exemplified by the human PDE10a-papaverine structure.

  2009cited by this paper
• Synthesis and in vitro antitumor activities of novel 4-anilinoquinazoline derivatives.

  2009cited by this paper
• Discovery of a series of 6,7-dimethoxy-4-pyrrolidylquinazoline PDE10A inhibitors.

  2007cited by this paper
• Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling.

  2007cited by this paper
• Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents.

  2006cited by this paper
• Multipotent antioxidants: from screening to design.

  2006cited by this paper
• Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use

  2006cited by this paper
• Cilostazol (pletal): a dual inhibitor of cyclic nucleotide phosphodiesterase type 3 and adenosine uptake.

  2006cited by this paper
• Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis.

  2006cited by this paper
• Genetic deletion of the striatum-enriched phosphodiesterase PDE10A: evidence for altered striatal function.

  2006cited by this paper
• Roflumilast: a selective phosphodiesterase 4 inhibitor.

  2005cited by this paper
• Cyclic nucleotide phosphodiesterases and their role in immunomodulatory responses: Advances in the development of specific phosphodiesterase inhibitors

  2005cited by this paper
• Extending applicability of the oxygen radical absorbance capacity (ORAC-fluorescein) assay.

  2004cited by this paper
• Striatal phosphodiesterase mRNA and protein levels are reduced in Huntington's disease transgenic mice prior to the onset of motor symptoms.

  2004cited by this paper
• Surflex: fully automatic flexible molecular docking using a molecular similarity-based search engine.

  2003influential reference
• Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules

  2003cited by this paper
• Cyclic nucleotide phosphodiesterases and their role in endocrine cell signaling.

  2002cited by this paper
• Development and validation of an improved oxygen radical absorbance capacity assay using fluorescein as the fluorescent probe.

  2001cited by this paper
• Role of sodium channel inhibition in neuroprotection: effect of vinpocetine.

  2000cited by this paper
• Isolation and characterization of a dual-substrate phosphodiesterase gene family : PDE 10 A

  1999cited by this paper
• Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A.

  1999cited by this paper
• Efficacy and tolerance of vinpocetine in ambulant patients suffering from mild to moderate organic psychosyndromes.

  1991cited by this paper
• Parkinson's disease and Alzheimer's disease: neurodegenerative disorders due to brain antioxidant system deficiency?

  1990cited by this paper

• AMELIORATIVE EFFECTS OF SELECTIVE PDE-10 INHIBITORS AGAINST KETAMINE-MEDIATED SCHIZOPHRENIC OUTCOMES IN MICE

  2026cites this paper
• Opportunities and perspectives of small molecular phosphodiesterase inhibitors in neurodegenerative diseases.

  2024cites this paper
• Shield Machine-like Substrate Walking Strategy-Based Pocket Engineering of F-Amine Dehydrogenase for Accessing Structurally Diverse Fused-Ring and Linked-Ring Aryl Ketones

  2024cites this paper
• Xanthine–Dopamine Hybrid Molecules as Multitarget Drugs with Potential for the Treatment of Neurodegenerative Diseases

  2023cites this paper
• Biotransformation of papaverine and in silico docking studies of the metabolites on human phosphodiesterase 10a.

  2020cites this paper
• Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases

  2020cites this paper
• Novel, potent, selective, and brain penetrant phosphodiesterase 10A inhibitors.

  2019cites this paper
• Advances in Discovery of PDE10A Inhibitors for CNS-Related Disorders. Part 2: Focus on Schizophrenia.

  2019cites this paper
• Synthesis, SAR study, and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as phosphodiesterase 10A inhibitors.

  2019cites this paper
• The Impact of Natural Compounds on the Treatment of Neurodegenerative Diseases

  2019cites this paper