Synthesis of Sulfonamide Tethered (Hetero)aryl ethylidenes as Potential Inhibitors of P2X Receptors: A Promising Way for the Treatment of Pain and Inflammation

Abstract

P2X receptors have the ability to regulate various physiological functions like neurotransmission, inflammatory responses, and pain sensation. Such physiological properties make these receptors a new target for the treatment of pain and inflammation. Several antagonists of P2X receptors have been studied for the treatment of neuropathic pain and neurodegenerative disorders but potency and selectivity are the major issues with these known inhibitors. Sulfonamide derivatives were reported to be potent inhibitors of P2X receptors. In this study, sulfonamide carrying precursor hydrazide was synthesized by a facile method that was subsequently condensed with methyl (hetero)arylketones to obtain a series of new (hetero)aryl ethylidenes. These compounds were screened for inhibitory potential against <i>h</i>-P2X2, <i>h</i>-P2X4, <i>h</i>-P2X5, and <i>h</i>-P2X7 receptors to find their potency and selectivity. Computational studies were performed to confirm the mode of inhibition as well as type of interaction between ligand and target site. In calcium signaling experiments, compound <b>6h</b> was found to be the most potent and selective inhibitor of <i>h</i>-P2X2 and <i>h</i>-P2X7 receptors with IC₅₀ ± standard error of the mean (SEM) values of 0.32 ± 0.01 and 1.10 ± 0.21 μM, respectively. Compounds <b>6a</b> and <b>6c</b> exhibited selective inhibition for <i>h</i>-P2X7 receptor, whereas <b>6e</b>, <b>7a</b>, and <b>7b</b> expressed selective inhibitions toward <i>h</i>-P2X2 receptor that were comparable to the positive control suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS).