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

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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 againsth-P2X2,h-P2X4,h-P2X5, andh-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, compound6hwas found to be the most potent and selective inhibitor ofh-P2X2 andh-P2X7 receptors with IC50± standard error of the mean (SEM) values of 0.32 ± 0.01 and 1.10 ± 0.21 μM, respectively. Compounds6aand6cexhibited selective inhibition forh-P2X7 receptor, whereas6e7a, and7bexpressed selective inhibitions towardh-P2X2 receptor that were comparable to the positive control suramin and pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS).

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Mahmood, A., Munir, R., Zia-Ur-Rehman, M., Javid, N., Shah, S. J. A., Noreen, L., … Iqbal, J. (2021). Synthesis of Sulfonamide Tethered (Hetero)aryl ethylidenes as Potential Inhibitors of P2X Receptors: A Promising Way for the Treatment of Pain and Inflammation. ACS Omega, 6(38), 25062–25075. https://doi.org/10.1021/acsomega.1c04302

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