pyrimidinones and Neurodegenerative-Diseases

Neuro-inflammation accompanies numerous neurological disorders and conditions where it can be associated with a progressive neurodegenerative pathology. In a similar manner, alterations in sphingolipid metabolism often accompany or are causative features in degenerative neurological conditions. These include dementias, motor disorders, autoimmune conditions, inherited metabolic disorders, viral infection, traumatic brain and spinal cord injury, psychiatric conditions, and more. Sphingolipids are major regulators of cellular fate and function in addition to being important structural components of membranes. Their metabolism and signaling pathways can also be regulated by inflammatory mediators. Therefore, as certain sphingolipids exert distinct and opposing cellular roles, alterations in their metabolism can have major consequences. Recently, regulation of bioactive sphingolipids by neuro-inflammatory mediators has been shown to activate a neuronal NADPH oxidase 2 (NOX2) that can provoke damaging oxidation. Therefore, the sphingolipid-regulated neuronal NOX2 serves as a mechanistic link between neuro-inflammation and neurodegeneration. Moreover, therapeutics directed at sphingolipid metabolism or the sphingolipid-regulated NOX2 have the potential to alleviate neurodegeneration arising out of neuro-inflammation.

Topics: AIDS Dementia Complex; Animals; Biological Products; Brain Diseases, Metabolic, Inborn; Drug Discovery; Encephalitis, Viral; Enzyme Activation; Enzyme Replacement Therapy; Humans; Inflammation; NADPH Oxidase 2; Naphthalenes; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurons; Oxidation-Reduction; Pyrimidinones; Reactive Oxygen Species; Sphingolipids; Zika Virus Infection

Sirtuins are a family of NAD+-dependent deacetylases (class III histone deacetylases). Seven mammalian sirtuins, SIRT1-7, are identified, as the functions and locations differ greatly. SIRT1 and SIRT2 locate in nucleus and cytoplasm, while SIRT3-5 in mitochondria. Sirtuins are not only involved in many important biological processes such as apoptosis, cellular senescence, endocrine signaling, glucose homeostasis, aging, and longevity, it can also control circadian clocks and mitochondrial biogenesis. Small molecules that can modulate the sirtuins activity have been shown to have potentials for treating many human diseases such as type II diabetes, cancer, rheumatoid arthritis, cardiovascular and other age-relating diseases. Some polyphenolic natural products such as Resveratrol, Fisetin, and Quercetin have demonstrated health benefits due to their SIRT1 activation effects. Some structurally diverse synthetic compounds, such as SRT1720, SRT1460, Selisistat (EX 527), and AGK2 were used as small molecular SIRT modulators (IC50 = 0.04-100 μM) to treat ischemic stroke, myocardial infarction, neurodegenerative diseases, cancer, aging, and obesity. In order to get better understanding of how the small molecules interact with the sirtuin, the small molecules that having SIRT inhibitory or activation effect, found by HTS or other modern medicinal chemistry techniques, are reviewed in this article.

Topics: Humans; Imidazoles; Naphthalenes; Neoplasms; Neurodegenerative Diseases; Polyphenols; Pyrimidinones; Resveratrol; Sirtuins; Small Molecule Libraries; Stilbenes; Triterpenes

Protein misfolding and inclusion body formations are common events in neurodegenerative diseases characterized by deposition of misfolded proteins inside or outside of neurons, and are commonly referred to as "protein misfolding neurodegenerative diseases" (PMNDs). These phenotypically diverse but biochemically similar aggregates suggest a highly conserved molecular mechanism of pathogenesis. These challenges are magnified by presence of mutations that render individual proteins subject to misfolding and/or aggregation. Cell proteostasis network and molecular chaperoning are maintaining cell proteome to preserve the protein folding, refolding, oligomerization, or disaggregation, and play formidable tasks to maintain the health of organism in the face of developmental changes, environmental insults, and rigors of aging. Maintenance of cell proteome requires the orchestration of major pathways of the cellular proteostasis network (heat shock response (HSR) in the cytosol and the unfolded protein response (UPR) in the endoplasmic reticulum). Proteostasis responses culminate in transcriptional and post-transcriptional programs that up-regulate the homeostatic mechanisms. Proteostasis is strongly influenced by the general properties of individual proteins for folding, misfolding, and aggregation. We examine a growing body of evidence establishing that when cellular proteostasis goes awry, it can be reestablished by deliberate chemical and biological interventions. We first try to introduce some new chemical approaches to prevent the misfolding or aggregation of specific proteins via direct binding interactions. We then start with approaches that employ chemicals or biological agents to enhance the general capacity of the proteostasis network. We finish with evidence that synergy is achieved with the combination of mechanistically distinct approaches to reestablish organ proteostasis. © 2016 BioFactors, 43(6):737-759, 2017.

Topics: Amyloidogenic Proteins; Animals; Chalcones; Endoplasmic Reticulum; Gene Expression Regulation; Heat-Shock Response; Humans; Hydrazones; Molecular Chaperones; Neurodegenerative Diseases; Neuroprotective Agents; Protein Aggregation, Pathological; Protein Folding; Proteostasis; Proteostasis Deficiencies; Pyrimidinones; Thiophenes; Unfolded Protein Response

Autophagy is the mass degradation system that removes long-lived proteins and malfunctioning organelles within the cell. Dysfunctional autophagic processes can cause various diseases such as cancer and neurodegenerative disorders, but the underlying mechanisms responsible for such events remain undefined. Small molecules that control autophagy could be powerful tools to reveal autophagy mechanisms, and to develop treatments for autophagy-related diseases including Alzheimer's disease, Parkinson's disease and various cancer types. This review discusses the small molecules that have been identified to control autophagy and how they can be used to understand signaling pathways important for autophagy in the context of chemical genomics.

Topics: Alzheimer Disease; Autophagy; Cell Death; Humans; Neurodegenerative Diseases; Parkinson Disease; Proteins; Pyrimidinones; Signal Transduction; Small Molecule Libraries; Structure-Activity Relationship; Thiophenes

Substitution of hazardous and often harmful organic solvents with "green" and "sustainable" alternative reaction media is always desirous. Ionic liquids (IL) have emerged as valuable and versatile liquids that can replace most organic solvents in a variety of syntheses. However, recently new types of low melting mixtures termed as Deep Eutectic Solvents (DES) have been utilized in organic syntheses. DES are non-volatile in nature, have sufficient thermal stability, and also have the ability to be recycled and reused. Hence DES have been used as alternative reaction media to perform different organic reactions. The availability of green, inexpensive and easy to handle alternative solvents for organic synthesis is still scarce, hence our interest in DES mediated syntheses. Herein we have investigated Biginelli reaction in different DES for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Monoamine oxidases and cholinesterases are important drug targets for the treatment of various neurological disorders such as Alzheimer's disease, Parkinson's disease, depression and anxiety. The compounds synthesized herein were evaluated for their inhibitory potential against these enzymes. Some of the compounds were found to be highly potent and selective inhibitors. Compounds 1 h and 1c were the most active monoamine oxidase A (MAO A) (IC

Topics: Acetylcholinesterase; Cholinesterase Inhibitors; Deep Eutectic Solvents; Dose-Response Relationship, Drug; Humans; Molecular Docking Simulation; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neurodegenerative Diseases; Neuroprotective Agents; Pyrimidinones; Structure-Activity Relationship

Pyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione derivatives were investigated as novel small molecule amplifiers of heat shock factor 1 transcriptional activity. Lead optimization led to the discovery of compound 4A-13, which displayed potent HSF1 activity under mild heat stress (EC(50)=2.5microM) and significant cytoprotection in both rotenone (EC(50)=0.23microM) and oxygen-glucose deprivation cell toxicity models (80% protection at 2.5microM).

Topics: Animals; Cell Line, Tumor; Chemistry, Pharmaceutical; DNA-Binding Proteins; Drug Design; Glucose; Heat Shock Transcription Factors; Humans; Models, Chemical; Molecular Chaperones; Neurodegenerative Diseases; Oxygen; Protein Conformation; Protein Folding; Pyrimidinones; Rats; Rotenone; Structure-Activity Relationship; Transcription Factors; Triazines; Uracil