8-Hydroxy-2-(1H-1,2,3-triazol-1-yl)-1,4-naphtoquinone derivatives inhibited P2X7 Receptor-Induced dye uptake into murine Macrophages

Pacheco, Paulo; Galvão, R.M.S.; Faria, Ana Flávia Martins; Ranke, Natalia Lidmar von; Rangel, Mary; Ribeiro, Tadeu; Bello, Murilo Lamim; Rodrigues, Carlos Rangel; Ferreira, Vı́tor F.; Rocha, David R. da; Faria, Robson Xavier

doi:10.1016/j.bmc.2018.11.036

Cited by 19 publications

(6 citation statements)

References 20 publications

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“…Thiadiazole 9f showed elevated potency and selectivity for inhibiting P2X7R function in vitro , low toxicity to mammalian cells, good solubility in aqueous solutions, low metabolic stability, and potent inhibition of acute inflammation. In comparison to other molecules described by our group (Gonzaga et al, 2017; Faria et al, 2018; Pacheco et al, 2018) or various other groups and companies (Pevarello et al, 2017), 9f showed compatible pharmacological properties. Therefore, this thiadiazole analog may be a good candidate to inhibit P2X7R with therapeutic activity in humans.…”

Section: Discussionmentioning

confidence: 46%

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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Section: Discussionmentioning

confidence: 46%

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

et al. 2019

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“…Some of the natural and synthetic compounds were found to inhibit histamine, IL-1β, IL-6, and TNF-α release, cyclooxygenase-2 (COX-2) activity, and reduce edema in the carrageenan model of inflammation [6]. Some synthetic 1,4-NQs were observed to effectively block the P2X7R functions in mouse neuronal and macrophage cells [7][8][9][10][11][12][13]. In this study, we proved that synthetic tetracyclic naphthoquinone-thioglucoside conjugate U-556, is able to effectively block the functioning of P2X7R in mouse macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…1,4-Naphthoquinones (1,4-NQs) are a class of natural and synthetic compounds with a broad variety of biological activities, including analgesic and anti-inflammatory properties [6]. It has been proven that some synthetic derivatives of the 1,4-naphthoquinoid nucleus are able to effectively bind P2X7 receptor and inhibit its functions in in vitro, in vivo, and in silico models [7][8][9][10][11]. As a result, this class of compounds has been considered the scaffold for the development of effective drugs blocking the functions of P2X7R.…”

Section: Introductionmentioning

confidence: 99%

Tetracyclic 1,4-Naphthoquinone Thioglucoside Conjugate U-556 Blocks the Purinergic P2X7 Receptor in Macrophages and Exhibits Anti-Inflammatory Activity In Vivo

Kozlovskiy

Pislyagin

Menchinskaya

et al. 2023

IJMS

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P2X7 receptors (P2X7Rs) are ligand-gated ion channels that play a significant role in inflammation and are considered a potential therapeutic target for some inflammatory diseases. We have previously shown that a number of synthetic 1,4-naphthoquinones are capable of blocking P2X7Rs in neuronal and macrophage cells. In the present investigation, we have demonstrated the ability of the tetracyclic quinone-thioglucoside conjugate U-556, derived from 1,4-naphthoquinone thioglucoside, to inhibit ATP-induced Ca2+ influx and YO-PRO-1 dye uptake, which indicates blocking P2X7R in RAW 264.7 macrophages. This process was accompanied by the inhibition of ATP-induced reactive oxygen species production in macrophages, as well as the macrophage survival strengthening under ATP toxic effects. Nevertheless, U-556 had no noticeable antioxidant capacity. Naphthoquinone-thioglucoside conjugate U-556 binding to the extracellular part of the P2X7R was confirmed by SPR analysis, and the kinetic characteristics of this complex formation were established. Computer modeling predicted that U-556 binds the P2X7R allosteric binding site, topographically similar to that of the specific A438079 blocker. The study of biological activity in in vivo experiments shows that tetracylic conjugate significantly reduces inflammation provoked by carrageenan. The data obtained points out that the observed physiological effects of U-556 may be due to its ability to block the functioning of the P2X7R.

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“…In recent years, our research group has focused on the identification of novel and more selective chemotypes of P2X7 receptor inhibitors. In particular, we reported several natural and synthetic compounds with potent antagonist activity toward P2X7R and ATP-induced inflammatory responses [ 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Recently, we reported the synthesis and biological evaluation of a group of naphthoquinones sulfonamide and sulfonate ester derivatives against Chikungunya virus (CHIKV).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Biological Evaluation and Molecular Modeling Studies of Naphthoquinone Sulfonamides and Sulfonate Ester Derivatives as P2X7 Inhibitors

et al. 2023

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ATP acts in the extracellular environment as an important signal, activating a family of receptors called purinergic receptors. In recent years, interest in the potential therapeutics of purinergic components, including agonists and antagonists of receptors, has increased. Currently, many observations have indicated that ATP acts as an important mediator of inflammatory responses and, when found in high concentrations in the extracellular space, is related to the activation of the P2X7 purinergic receptor. In this sense, the search for new inhibitors for this receptor has attracted a great deal of attention in recent years. Sulfonamide derivatives have been reported to be potent inhibitors of P2X receptors. In this study, ten naphthoquinone sulfonamide derivatives and five naphthoquinone sulfonate ester derivatives were tested for their inhibitory activity on the P2X7 receptor expressed in peritoneal macrophages. Some compounds showed promising results, displaying IC50 values lower than that of A740003. Molecular docking and dynamic studies also indicated that the active compounds bind to an allosteric site on P2X7R. The binding free energy indicates that sulfonamides have an affinity for the P2X7 receptor similar to A740003. Therefore, the compounds studied herein present potential P2X7R inhibition.

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8-Hydroxy-2-(1H-1,2,3-triazol-1-yl)-1,4-naphtoquinone derivatives inhibited P2X7 Receptor-Induced dye uptake into murine Macrophages

Cited by 19 publications

References 20 publications

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

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

Tetracyclic 1,4-Naphthoquinone Thioglucoside Conjugate U-556 Blocks the Purinergic P2X7 Receptor in Macrophages and Exhibits Anti-Inflammatory Activity In Vivo

Synthesis, Biological Evaluation and Molecular Modeling Studies of Naphthoquinone Sulfonamides and Sulfonate Ester Derivatives as P2X7 Inhibitors

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