Synthesis, characterization and biological evaluation of indomethacin derived thioureas as purinergic (P2Y1, P2Y2, P2Y4, and P2Y6) receptor antagonists

Bano, Sehrish; Shabir, Ghulam; Saeed, Aamer; Ul‐Hamid, Anwar; Alharthy, Rima D.; Iqbal, Jamshed

doi:10.1016/j.bioorg.2021.105378

Cited by 7 publications

(3 citation statements)

References 25 publications

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“…The last relevant modification on the carboxylic acid moiety came in 2021 by Iqbal. [39] In this work, the use of aryl thioureas bonded to the carbonyl group of carboxylic acid in the indomethacin, allowed the synthesis of different derivatives 75-77. These functionalized indomethacin derivatives were tested as purinergic P2Y receptor agonists.…”

Section: Modifications On the Carboxyl Group Of Indomethacinmentioning

confidence: 99%

Indomethacin Synthesis, Historical Overview of Their Structural Modifications

et al. 2022

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One of the most important (NSAID) non-steroidal anti-inflammatory drug-containing the indol core is represented by the indomethacin. This highly relevant compound has been used for the last 50 years with excellent pharmacological results. Due to its relevant efficacy as an anti-inflammatory treatment, several syntheses have been developed during this half of century. Herein is summarized and discussed the most representative strategies which successfully addressed the total syntheses of indomethacin as well as some of its derivatives generated by carrying out strategic modifications at the nitrogen atom, the carboxylic acid at C-3, the methoxy group at C-5 and the methyl group at C-2.[a] K.

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Section: Modifications On the Carboxyl Group Of Indomethacinmentioning

confidence: 99%

Indomethacin Synthesis, Historical Overview of Their Structural Modifications

et al. 2022

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“…Also, is one of the most important NSAID‐containing the indol core, broadly used the last half century. Due to its efficacy as anti‐inflammatory, several strategies have been developed for its total synthesis [27] as well as some structural modifications at the carboxylic acid, [28–32] C‐2, [33,34] C‐5 [35] and nitrogen [36–37] (Figure 1B). One of the main indomethacin inconveniences is the adverse effects on the gastrointestinal (GI) tract due to the action over COX‐1 [38,39] …”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anti‐inflammatory Effect of Simple 2,3‐Diarylindoles. On Route to New NSAID Scaffolds

Segura‐Quezada,

Alba‐Betancourt,

Chacón‐García

et al. 2024

ChemistrySelect

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Nitrogen‐containing drugs represent one of the worldwide most extensive sources of treatments for different diseases. Indomethacin as example, is one of the most important non‐steroidal anti‐inflammatories (NSAID) indol‐containing drug. Its relevance has been demonstrated the last 50 years with excellent pharmacological results. Its efficacy as an anti‐inflammatory treatment, inspired us the exploration of indol‐containing structurally less elaborated compounds which kept and/or improve the anti‐inflammatory activity compared with indomethacin. Herein is summarized and discussed our initial findings on the synthesis and anti‐inflammatory effect of different 2,3‐diarylindoles, designed for strategically favoring the plausible and selective interactions with COX‐2, on route to new simple NSAID scaffolds. The TPA model and formalin test were used in this study to generate inflammation in mice for conducting the assays with the synthesized 2,3‐diarylindoles. Docking analysis revealed stronger N−H indolic interactions with COX‐2 for 6‐methoxy‐2‐phenyl‐3‐(4‐chlorophenyl)‐1H‐indole, one of the most active of the synthesized compounds when compared with indomethacin. This, experimentally match with the anti‐inflammatory observed effect and putatively indicates the biochemical action mechanism.

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“…Therefore, there is need for development and synthesis of P2Y1R antagonists with enhanced pharmaceutical features. Elinogrel,SAR216471, Suramin, Reactive Blue-2, Butylphenoxy-(trifluoromethoxy) phenylurea (BPTU), MRS2500 and Pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid [PPADS] are some stated inhibitors of P2YRs as shown in Figure 1 (Oestreich, 2010;Boldron et al, 2014;Peng et al, 2018;Bano et al, 2021). Recently, Benzimidazole-4,7-dione-based analogues were reported as a new class of compounds for the development of P2X3R antagonists (Bae et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, structure-activity relationships and biological evaluation of benzimidazole derived sulfonylurea analogues as a new class of antagonists of P2Y1 receptor

et al. 2023

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The P2Y receptors are responsible for the regulation of various physiological processes including neurotransmission and inflammatory responses. These receptors are also considered as novel potential therapeutic targets for prevention and treatment of thrombosis, neurological disorders, pain, cardiac diseases and cancer. Previously, number of P2Y receptor antagonists has been investigated but they are less potent and non-selective with poor solubility profile. Herein, we present the synthesis of new class of benzimidazole derived sulfonylureas (1a-y) as potent antagonists of P2Y receptors, with the specific aim to explore selective antagonists of P2Y1 receptors. The efficacy and selectivity of the synthesized derivatives 1) against four P2Y receptors i.e., t-P2Y1, h-P2Y2, h-P2Y4, and r-P2Y6Rs was carried out by calcium mobilization assay. The results revealed that except 1b, 1d, 1l, 1m, 1o, 1u, 1v, 1w, and 1y, rest of the synthesized derivatives exhibited moderate to excellent inhibitory potential against P2Y1 receptors. Among the potent antagonists, derivative 1h depicted the maximum inhibition of P2Y1 receptor in calcium signalling assay, with an IC50 value of 0.19 ± 0.04 µM. The potential of inhibition was validated by computational investigations where bonding and non-bonding interactions between ligand and targeted receptor further strengthen the study. The best identified derivative 1h revealed the same binding mechanism as that of already reported selective antagonist of P2Y1 receptor i.e (1-(2- (2-tert-butyl-phenoxy) pyridin-3-yl)-3–4-(trifluoromethoxy) phenylurea but the newly synthesized derivative exhibited better solubility profile. Hence, this derivative can be used as lead candidate for the synthesis of more potential antagonist with much better solubility profile and medicinal importance.

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Synthesis, characterization and biological evaluation of indomethacin derived thioureas as purinergic (P2Y1, P2Y2, P2Y4, and P2Y6) receptor antagonists

Cited by 7 publications

References 25 publications

Indomethacin Synthesis, Historical Overview of Their Structural Modifications

Indomethacin Synthesis, Historical Overview of Their Structural Modifications

Synthesis and Anti‐inflammatory Effect of Simple 2,3‐Diarylindoles. On Route to New NSAID Scaffolds

Synthesis, structure-activity relationships and biological evaluation of benzimidazole derived sulfonylurea analogues as a new class of antagonists of P2Y1 receptor

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