Arylboronic acids inhibit P2X7 receptor function and the acute inflammatory response

Faria, Robson Xavier; Hiller, Noemi de Jesus; Salles, Juliana; Resende, Jackson A. L. C.; Diogo, R; Ranke, Natalia Lidmar von; Bello, Murilo Lamim; Rodrigues, Carlos Rangel; Castro, Helena C.; Martins, Daniela de Luna

doi:10.1007/s10863-019-09802-x

Cited by 16 publications

(9 citation statements)

References 72 publications

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“…P2X7R has been widely studied as a target for anti-inflammatory disorders. The experimental models used in this work helped us to understand the mechanism of action of triazole-derived molecules toward P2X7R, as previously reported [ 45 , 46 ], by showing their inhibitory potential against P2X7R-mediated inflammatory processes in vivo.…”

Section: Discussionmentioning

confidence: 72%

Triazoles with inhibitory action on P2X7R impaired the acute inflammatory response in vivo and modulated the hemostatic balance in vitro and ex vivo

et al. 2022

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Objective The present study aimed to investigate five triazole compounds as P2X7R inhibitors and evaluate their ability to reduce acute inflammation in vivo. Material The synthetic compounds were labeled 5e , 8h , 9i , 11 , and 12 . Treatment We administered 500 ng/kg triazole analogs in vivo, (1–10 µM) in vitro, and 1000 mg/kg for toxicological assays. Methods For this, we used in vitro experiments, such as platelet aggregation, in vivo experiments of paw edema and peritonitis in mice, and in silico experiments. Results The tested substances 5e , 8h , 9i , 11 , and 12 produced a significant reduction in paw edema. Molecules 5e , 8h , 9i , 11 , and 12 inhibited carrageenan-induced peritonitis. Substances 5e , 8h , 9i , 11 , and 12 showed an anticoagulant effect, and 5e at a concentration of 10 µM acted as a procoagulant. All derivatives, except for 11 , had pharmacokinetic, physicochemical, and toxicological properties suitable for substances that are candidates for new drugs. In addition, the ADMET risk assessment shows that derivatives 8h , 11 , 5e , and 9i have high pharmacological potential. Finally, docking tests indicated that the derivatives have binding energies comparable to the reference antagonist with a competitive inhibition profile. Conclusions Together, the results indicate that the molecules tested as antagonist drugs of P2X7R had anti-inflammatory action against the acute inflammatory response. Supplementary Information The online version contains supplementary material available at 10.1007/s00011-022-01664-1.

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Section: Discussionmentioning

confidence: 72%

Triazoles with inhibitory action on P2X7R impaired the acute inflammatory response in vivo and modulated the hemostatic balance in vitro and ex vivo

et al. 2022

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“…Three-dimensional structures of the diterpenes were built and optimized using SPARTAN’10 software as described in previous works [ 25 , 26 ].…”

Section: Methodsmentioning

confidence: 99%

“…The superposition of the A740003 conformation extracted from PDB ID: 5U1U and the most favorable conformation generated by blind molecular docking are shown in Supplementary Figure S1 . The methods for molecular docking have been described in previous reports [ 25 , 26 , 28 ].…”

Section: Methodsmentioning

confidence: 99%

Eugenia sulcata (Myrtaceae) Nanoemulsion Enhances the Inhibitory Activity of the Essential Oil on P2X7R and Inflammatory Response In Vivo

et al. 2022

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P2X7R is a purinergic receptor with broad expression throughout the body, especially in immune system cells. P2X7R activation causes inflammatory mediators to release, including interleukin-1β (IL-1β), the processing and release of which are critically dependent on this ion channel activation. P2X7R’s therapeutic potential augments the discovery of new antagonistic compounds. Thus, we investigated whether the Eugenia sulcata essential oil could block P2X7R activity. The essential oil (ESO) dose-dependently inhibited ATP-promoted PI uptake and IL-1β release with an IC50 of 113.3 ± 3.7 ng/mL and 274 ± 91 ng/mL, respectively, and the essential oil nanoemulsion (ESON) improved the ESO inhibitory effect with an IC50 of 81.4 ± 7.2 ng/mL and 62 ± 2 ng/mL, respectively. ESO and ESON reversed the carrageenan-activated peritonitis in mice, and ESON exhibited an efficacy higher than ESO. The majority substance from essential oil, β-caryophyllene, impaired the ATP-evoked PI uptake and IL-1β release with an IC50 value of 26 ± 0.007 ng/mL and 97 ± 0.012 ng/mL, respectively. Additionally, β-caryophyllene reduced carrageenan-induced peritonitis, and the molecular modeling and computational simulation predicted the intermolecular interactions in the P2X7R situs. In silico, results indicated β-caryophyllene as a potent allosteric P2X7R antagonist, although this substance may present toxic effects for humans. These data confirm the nanoemulsion of essential oil from E. sulcata as a promisor biotechnology strategy for impaired P2X7R functions and the inflammatory response.

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“…The boron-containing compounds were compared to their respective carbon analogues which were not as effective, suggesting that boron plays a critical role in the inhibition process [ 124 ]. In a different study, a series of boronic acid P2X7R inhibitors as anti-inflammatories were able to inhibit P2X7R through antagonistic mechanisms, outperforming other P2X7R inhibitors such as BBG and A740003, at reducing P2X7R activity and inflammation [ 125 ]. In another study, SX-517 ( Table 5 ) was the first reported boronic acid chemokine antagonist for CXCR 1 and 2 and was able to significantly inhibit inflammation in vivo [ 126 ].…”

Section: Boron Medicinal Chemistrymentioning

confidence: 99%

The Boron Advantage: The Evolution and Diversification of Boron’s Applications in Medicinal Chemistry

2022

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In this review, the history of boron’s early use in drugs, and the history of the use of boron functional groups in medicinal chemistry applications are discussed. This includes diazaborines, boronic acids, benzoxaboroles, boron clusters, and carboranes. Furthermore, critical developments from these functional groups are highlighted along with recent developments, which exemplify potential prospects. Lastly, the application of boron in the form of a prodrug, softdrug, and as a nanocarrier are discussed to showcase boron’s emergence into new and exciting fields. Overall, we emphasize the evolution of organoboron therapeutic agents as privileged structures in medicinal chemistry and outline the impact that boron has had on drug discovery and development.

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Arylboronic acids inhibit P2X7 receptor function and the acute inflammatory response

Cited by 16 publications

References 72 publications

Triazoles with inhibitory action on P2X7R impaired the acute inflammatory response in vivo and modulated the hemostatic balance in vitro and ex vivo

Triazoles with inhibitory action on P2X7R impaired the acute inflammatory response in vivo and modulated the hemostatic balance in vitro and ex vivo

Eugenia sulcata (Myrtaceae) Nanoemulsion Enhances the Inhibitory Activity of the Essential Oil on P2X7R and Inflammatory Response In Vivo

The Boron Advantage: The Evolution and Diversification of Boron’s Applications in Medicinal Chemistry

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