1,4-Naphthoquinones potently inhibiting P2X7 receptor activity

Faria, Robson Xavier; Oliveira, Felipe H.; Salles, Juliana; Oliveira, Anabela S.; Ranke, Natalia Lidmar von; Bello, Murilo Lamim; Rodrigues, Carlos Rangel; Castro, Helena C.; Louvis, A.R.; Martins, Daniela de Luna; Ferreira, Vı́tor F.

doi:10.1016/j.ejmech.2017.10.033

Cited by 29 publications

(33 citation statements)

References 46 publications

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“…Compound (25) has significant anti-inflammatory properties that inhibit LPS-induced cytokine production in human mononuclear cell lines THP-1 and block the production of TNF-α and interleukin (IL)-6 with an IC 50 of 0.60 and 0.06 µM respectively, while (26) was inactive. 50) To date, a number of new 3-halogen and 3-aryl-2-hydroxy-1,4-naphthoquinones have been synthesized, among which a new class of effective inhibitors of P2X7 receptors has been established. 51) In fact, currently this is the first published work demonstrating the effective anti-inflammatory and analgesic activity of 1,4-naphthoquinones associated with the blocking of P2X7 receptors.…”

Section: Cardioprotective and Anti-ischemic Propertiesmentioning

confidence: 99%

1,4-Naphthoquinones: Some Biological Properties and Application

2020

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Over the past decade, a number of new 1,4-naphthoquinones have been isolated from natural sources and new 1,4-naphthoquinones with diverse structural features have been synthesized. Cardioprotective, antiischemic, hepatoprotective, neuroprotective and some other new properties were found for these compounds; their role in protecting against neurodegenerative diseases has been established. Their anti-inflammatory, antimicrobial and antitumor activities have been studied in more detail; new, previously unknown intracellular molecular targets and mechanisms of action have been discovered. Some compounds of this class are already being used as a medicinal drugs and some substances can be used as biochemical tools and probes for non-invasive detection of pathological areas in cells and tissues in myocardial infarction and neurodegenerative diseases using modern molecular imaging techniques.

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Section: Cardioprotective and Anti-ischemic Propertiesmentioning

confidence: 99%

1,4-Naphthoquinones: Some Biological Properties and Application

2020

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“…HEK-293 cells expressing human P2X7R were maintained in Dulbecco's modified Eagle's medium (DMEM; Sigma-Aldrich) supplemented with 10% fetal bovine serum (FBS; Prolab, Br) and anti-biotics (50 U/ml penicillin and 50 mg/ml streptomycin) in a humidified 5% CO 2 atmosphere at 37°C (Faria et al, 2018). A total of 5 × 10 5 cells were plated at 37°C in a humidified 5% CO 2 atmosphere for 24 h in a 96-well plate for dye uptake or IL-1β release assays.…”

Section: Biological Assaysmentioning

confidence: 99%

Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Thiadiazole Derivatives as Potent P2X7 Receptor Inhibitors

et al. 2019

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Twenty new 2-(1 H -pyrazol-1-yl)-1,3,4-thiadiazole analogs were synthetized to develop P2X7 receptor (P2X7R) inhibitors. P2X7R inhibition in vitro was evaluated in mouse peritoneal macrophages, HEK-293 cells transfected with hP2X7R (dye uptake assay), and THP-1 cells (IL-1β release assay). The 1-(5-phenyl-1,3,4-thiadiazol-2-yl)-1 H -pyrazol-5-amine derivatives 9b , 9c , and 9f , and 2-(3,5-dimethyl-1 H -pyrazol-1-yl)-5-(4-fluorophenyl)-1,3,4-thiadiazole ( 11c ) showed inhibitory effects with IC 50 values ranging from 16 to 122 nM for reduced P2X7R-mediated dye uptake and 20 to 300 nM for IL-1β release. In addition, the in vitro ADMET profile of the four most potent derivatives was determined to be in acceptable ranges concerning metabolic stability and cytotoxicity. Molecular docking and molecular dynamics simulation studies of the molecular complexes human P2X7R/ 9f and murine P2X7R/ 9f indicated the putative intermolecular interactions. Compound 9f showed affinity mainly for the Arg268, Lys377, and Asn266 residues. These results suggest that 2-(1 H -pyrazol-1-yl)-1,3,4-thiadiazole analogs may be promising novel P2X7R inhibitors with therapeutic potential.

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“…The P2X7 receptor is a ligand-dependent ion channel that belongs to the type 2 purinergic receptor family (P2) [1]. The P2 receptor family comprises the P2Y G protein-coupled receptors (P2Y1, 2,4,6,[11][12][13][14] and the P2X (P2X1-7) receptors, which are ion channels regulated by ligand. P2X7 is the receptor subtype most widely studied from an immunological perspective [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…P2X7R inhibiting substances have been used as therapeutic agents [12,13]. However, clinical trials in patients with rheumatoid arthritis using AZD-9056 and CE-224535 showed no improvement in the disease compared to the current clinical treatment.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, arises the need to try new selective inhibitors for this receptor. Consequently, the use of quinones, which is found in nature, could be a good response to this need [13,14]. For which it is essential to know the type of molecular interaction using a theoretical study of the electronic structure of the 2-hydroxy-1,4-naphthoninone derivatives (Table 2) and their possible interaction with the P2X7R receptor, to obtain information, from this biological process.…”

Section: Introductionmentioning

confidence: 99%

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Theoretical Analysis of the Relationship Between the Electronic Structure and Its Inhibitory Action in the P2x7r Receptor of a Series of 2-Hydroxy-1,4-Naphthoquinones Derivatives

Ardiles

Vega

2018

J. Chil. Chem. Soc.

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In this work, a theoretical study of the relationship between the electronic structure and the activity of the P2X7R receptor from 2-hydroxy-1,4-naphthoquinone derivatives, using the KPG method, was performed. The electronic structure of the molecules was calculated at level B3LYP / 6-31G (d, p) with full geometry optimization. A statistically significant equation was obtained by relating the variation of biological activity with the variation of a set of indices of local atomic reactivity. Based on the analysis of the results, a two-dimensional pharmacophore was proposed.

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1,4-Naphthoquinones potently inhibiting P2X7 receptor activity

Cited by 29 publications

References 46 publications

1,4-Naphthoquinones: Some Biological Properties and Application

1,4-Naphthoquinones: Some Biological Properties and Application

Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Thiadiazole Derivatives as Potent P2X7 Receptor Inhibitors

Theoretical Analysis of the Relationship Between the Electronic Structure and Its Inhibitory Action in the P2x7r Receptor of a Series of 2-Hydroxy-1,4-Naphthoquinones Derivatives

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