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 h-P2X2, h-P2X4, h-P2X5, and h-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 6h was found to be the most potent and selective inhibitor of h-P2X2 and h-P2X7 receptors with IC50 ± standard error of the mean (SEM) values of 0.32 ± 0.01 and 1.10 ± 0.21 μM, respectively. Compounds 6a and 6c exhibited selective inhibition for h-P2X7 receptor, whereas 6e, 7a, and 7b expressed selective inhibitions toward h-P2X2 receptor that were comparable to the positive control suramin and pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS).

2,1-Benzothiazine – (quinolin/thiophen)yl hydrazone frameworks as new monoamine oxidase inhibitory agents; synthesis, in vitro and in silico investigation

“…The N -sulphonylated ester 2 obtained by solvent-free N -mesylation of methyl anthranilate 1 upon N -methylation lead to the formation of ester 3. 29 Subsequent base catalyzed ring closure of the ester 3 resulted in the formation of ketone 4 with 2,1-benzothiazine framework which was further condensed with hydrazine monohydrate to yield hydrazone 5 in excellent yield. Finally, the acid catalyzed reaction of hydrazone 5 with (un)substituted 2-chloroquinoline carbaldehydes 6(a–f) and methyl-thiophenyl ketones 8(a–k) in methanol resulted in the formation of new titled compounds 7(a–f) and 9(a–k) correspondingly in reasonably good yields.…”

“…Compounds 2-4 and 6 were synthesized by procedures reported in literature. 29,31 Synthesis of 4-hydrazono-1-methyl-3,4-dihydro-1H-benzo[c] [1,2]thiazine 2,2-dioxide ( 5) [1,2]thiazin-4(3H)-one 2,2dioxide 4 (25 mmol; 5.275 g) and 64% hydrazine monohydrate (75 mmol; 5.86 g, 5.7 mL) in absolute ethanol (50 mL) was heated under reux conditions for 8 hours. The progress of reaction was monitored by TLC until the reactant spot disappeared.…”

“…1). 26,27 In continuation of our efforts to search for new bioactive synthetic compounds, [28][29][30] we herein report the synthesis of new 2,1-benzothiazine 2,2-dioxide analogues and evaluation of their monoamine oxidase (MAO A and MAO B) inhibitory potential. To validate the results, in silico docking studies have been conducted to assess the binding interaction of the synthesized compounds inside the active site of enzyme.…”

Rehabilitation of the P2X5 receptor: a re-evaluation of structure and function

“…Soon afterwards, the human exon 10 sequence was confirmed by a second research group when probing human genomic DNA with the exon 10 cDNA sequence for rP2X5 [14]. A full-length construct of human P2X5 was prepared for expression studies and the resultant full-length protein (444 aa subunit) assembled into a functional hP2X5 receptor [14, and then see [15][16][17][18]. However, the primary sequence of the full-length human P2X5 protein (hP2X5-fl) has never been listed in popular databases (such as Ensembl and Uni-portKB).…”

“…Also, the cDNA for hP2X5-fl was not readily available and each laboratory was required to generate a construct with the exon 10 coding region correctly inserted into the cDNA of canonical hP2X5A. So far, only four laboratories have succeeded in generating this construct and then characterised the resultant full length hP2X5 receptors [see 13,[15][16][17][18]. The results of these functional studies are summarised in Table 1.…”