Abstract
The P2X7 receptor (P2X7R) is an ion channel that promotes the passage of ions through the membrane through brief stimulation once activated by ATP, its endogenous opener. However, prolonged stimulation with ATP, which occurs in pathological processes, opens a nonselective pore in the plasma membrane, allowing the passage of large molecules and leading to cytokine release or even cell death. In this sense, the search for new inhibitors for this receptor has attracted a great deal of attention in recent years. Considering the booming of biomass upgrading reactions in recent years and the continued efforts to synthesize biologically active molecules containing the 1,2,3-triazole ring, in the present work, we aimed to investigate whether triazole-linked menadione-furan derivatives could present P2X7R inhibitory activity. The novel compounds were tested for their inhibitory activity on ATP-induced dye uptake in peritoneal macrophages. Some have shown promising results, having displayed IC50 values lower than that of the P2X7R inhibitor BBG. Molecular docking studies also indicated that the active compounds bind to an allosteric site on P2X7R, presenting potential P2X7R inhibition.
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Data availability
The authors declare that all data supporting the findings of this study are available within the article and its supplementary information files.
Abbreviations
- ATP:
-
Adenosine triphosphate
- ATPe:
-
Extracelular ATP
- BBG:
-
Brilliant Blue G
- CINC-1:
-
Cytokine-induced neutrophil chemoattractant-1
- Da:
-
Dalton
- DMSO:
-
Dimethyl sulfoxide
- FBS:
-
Fetal bovine serum
- FP:
-
Hybrid substances nomenclature
- IL-1β:
-
Interleukin-1β
- IL-6:
-
Interleukin-6
- P2X7R:
-
P2X7 Receptor
- PBS:
-
Phosphate-Buffered Saline
- PI:
-
Propidium iodide
- TNF-α:
-
Tumor necrosis fator alfa
- Tx:
-
Triton X-100
- VEGF:
-
Vascular endothelial growth factor
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Acknowledgements
We thank the IOC, LABTOXo and LAPSA for their support.
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The fellowships granted by CNPq (301873/2019–4, 308755/2018–9 and 306011/2020–4), CAPES (Financial Code 001) and FAPERJ (E-26/203.246/2017, E-26/211.025/2019, E-26/200.982/2021, E-26/203.191/2017, E-26/202.800/2017, E-26/010.101106/2018, E-26/200.870/2021, E-26/201.369/2021 and SEI-260003/001178/2020) are gratefully acknowledged.
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J.P. S.S and J.V.F.- these authors did the biological assays. R.C.B.R. and M.L.B.—these authors did the in-silico assays. C.G.S.L., F.P. P., A.A.B.—these authors synthetized the molecules. D.R.P., M.G.M., L.S.M.F., V.F.F., and F.C.S.—these authors—prepare the figures, coordinated the synthesis assays, wrote, and revised the paper. R.X.F.—this author revised the biological assays, wrote, and revised the paper.
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dos Santos, J.P.S., Ribeiro, R.C.B., Faria, J.V. et al. Synthesis, biological evaluation and molecular modeling studies of novel 1,2,3-triazole-linked menadione-furan derivatives as P2X7 inhibitors. J Bioenerg Biomembr 54, 227–239 (2022). https://doi.org/10.1007/s10863-022-09947-2
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DOI: https://doi.org/10.1007/s10863-022-09947-2