In silico and pharmacological study of N,S-acetal juglone derivatives as inhibitors of the P2X7 receptor-promoted in vitro and in vivo inflammatory response

Purinergic receptors are transmembrane proteins responsive to extracellular nucleotides and are expressed by several cell types throughout the human body. Among all identified subtypes, the P2×7 receptor has emerged as a relevant target for the treatment of inflammatory disease. Several clinical trials have been conducted to evaluate the effectiveness of P2×7R antagonists. However, to date, no selective antagonist has reached clinical use. In this work, we report the pharmacological evaluation of eleven N, S-acetal juglone derivatives as P2×7R inhibitors. Using in vitro assays and in vivo experimental models, we identified one derivative with promising inhibitory activity and low toxicity. Our in silico studies indicate that the 1,4-naphthoquinone moiety might be a valuable molecular scaffold for the development of novel P2×7R antagonists, as suggested by our previous studies. [Display omitted] •P2X7 receptor (P2X7R) is an ATP-gated ion channel involved in several inflammatory diseases and neuropathic pain.•P2X7R activation triggers several pro-inflammatory mechanisms, such as NLRP3 inflammasome assembly and release of IL-1β.•Despite the key role of P2X7R in inflammatory disorders, no inhibitor is approved for clinical use yet.•Juglone-derived N,S-acetal compounds showed good in vitro and in vivo P2X7R inhibitory activity.•In silico studies corroborates that 1,4-naphthoquinones might be valuable synthetic platforms for novel P2X7 antagonists.