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

Abstract

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.

Ruscogenin Ameliorated Sjögren’s Syndrome by Inhibiting NLRP3 Inflammasome Activation

“…P2X7R is taken as a pivotal receptor in inflammation, whose activation positively connects with the maturation and release of pro-inflammatory molecules like IL-1 β . In addition, P2X7R is verified to cause inflammatory reactions and exacerbate the prognosis through strongly activating NLRP3 inflammasome [ 36 – 39 ]. Similar to the study about Ruscogenin in blood-brain barrier dysfunction [ 23 ], our research viewed that Ruscogenin repressed P2X7R, NLRP3, caspase 1, and IL-1 β expression in SS mice models in a dose-dependent manner, which implicated that the protective effect of Ruscogenin against SS might be associated with NLRP3 inflammasome.…”

Does Cholinergic Stimulation Affect the P2X7 Receptor-Mediated Dye Uptake in Mast Cells and Macrophages?

“…In mice lacking P2X7 receptors, ATP does not lead to release of IL-1β from LPS-primed cells (Solle et al, 2001 ). Consistent with this finding, the research groups are searching for the novel efficient P2X7 antagonists to counteract the excessive neuroinflammation (Gonzaga et al, 2019 ). The prominent property of the P2X7 receptor subtype is the opening of the large pore permeable to cationic dyes such as YO-PRO1 and ethidium bromide (EtBr; North, 2002 ).…”

Inflammatory Mediators Leading to Edema Formation through Plasma Membrane Receptors

“…The IL-1β inhibition in inflammation and pain has been addressed in several inflammation studies. Experiments in vivo using P2X7R antagonist have demonstrated improvements in the swelling caused by inflammation in a model of paw edema [97,98]. The pain sensibility mechanism is linked to vascular permeability, causing edema [2].…”