Design and synthesis of pyrimidine-5-carbonitrile hybrids as COX-2 inhibitors: Anti-inflammatory activity, ulcerogenic liability, histopathological and docking studies

Alfayomy, Abdallah M.; Abdel‐Aziz, Salah A.; Marzouk, Adel A.; Shaykoon, Montaser Sh. A.; Narumi, Atsushi; Konno, Hiroyuki; Abou‐Seri, Sahar M.; Ragab, F. M.

doi:10.1016/j.bioorg.2020.104555

Cited by 39 publications

(28 citation statements)

References 44 publications

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“…Despite the presence of several NSAIDs, the development of new NSAIDs is attractive, owing to the diverse inflammatory conditions and the need for optimized application in relation to disease and patient conditions. The recent development of NSAIDs comprises modified methyl sulphonyl [ 17 ]; pyrimidine-5-carbonitrile hybrids [ 18 ], pyrazole derivatives [ 19 ], indanone containing spiroisoxazoline derivatives [ 20 ], triazole, and oxadiazole compounds [ 21 , 22 ]. Despite the growing repository of newly synthesized NSAIDs, the development of new compounds is strictly required due to the side effects of the currently approved NSAIDs.…”

Section: Discussionmentioning

confidence: 99%

Drug Discovery of New Anti-Inflammatory Compounds by Targeting Cyclooxygenases

2022

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The goal of achieving anti-inflammatory efficacy with the fewest possible adverse effects through selective COX-2 inhibition is still being investigated in order to develop drugs with safe profiles. This work shows the efficacy and safety profile of two novel benzimidazole piperidine and phenoxy pyridine derivatives in reaching this goal, which would be considered a major achievement in inflammatory therapy. The compounds were evaluated by virtual screening campaign, in vitro cyclooxygenase 1 and 2 (COX-1 and COX-2) inhibition, in vivo carrageenan-induced rat paw edema assay, cytotoxicity against Raw264.7 cells, and histopathological examination of rat paw and stomach. Two new compounds, compound 1 ([(2-{[3-(4-methyl-1H-benzimidazol-2-yl)piperidin-1-yl]carbonyl}phenyl)amino]acetic acid) and compound 2 (ethyl 1-(5-cyano-2-hydroxyphenyl)-4-oxo-5-phenoxy-1,4-dihydropyridine-3-carboxylate) showed high selectivity against COX-2, favourable drug-likeness and ADME descriptors, a lack of cytotoxicity, relived paw edema, and inflammation without noticeable side effects on the stomach. These two compounds are promising new NSAIDs.

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Section: Discussionmentioning

confidence: 99%

Drug Discovery of New Anti-Inflammatory Compounds by Targeting Cyclooxygenases

2022

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“…The in vivo anti-inflammatory activity study of COX-2 inhibitors indicated that the anti-inflammatory activity of compound 54 was higher than that of the reference drug celecoxib. In addition, it showed better safety compared to celecoxib in the ulcerogenic liability test 69 .…”

Section: Recent Development In Anti-inflammatory Agentsmentioning

confidence: 99%

“…Alfayomy et al. 69 prepared two new series of 1,3,4-oxadiazole and coumarin derivatives based on pyrimidine-5-carbonitrile scaffold, and then assessed their COX-1/COX-2 inhibitory activity. Compound 54 ( Figure 6 ) was found to be the most potent and selective inhibitor of COX-2 (IC 50 =0.081 µM, SI = 170.37).…”

Section: Recent Development In Anti-inflammatory Agentsmentioning

confidence: 99%

Small molecule compounds with good anti-inflammatory activity reported in the literature from 01/2009 to 05/2021: a review

Bian

Wu³

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Inflammation and disease are closely related. Inflammation can induce various diseases, and diseases can promote inflammatory response, and two possibly induces each other in a bidirectional loop. Inflammation is usually treated using synthetic anti-inflammatory drugs which are associated with several adverse effects hence are not safe for long-term use. Therefore, there is need for anti-inflammatory drugs which are not only effective but also safe. Several researchers have devoted to the research and development of effective anti-inflammatory drugs with little or no side effects. In this review, we studied some small molecules with reported anti-inflammatory activities and hence potential sources of anti-inflammatory agents. The information was retrieved from relevant studies published between January 2019 and May, 2021 for review. This review study was aimed to provide relevant information towards the design and development of effective and safe anti-inflammation agents.

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“…According to the reported procedures for carrageenan-induced paw edoema test in mice 51 , this test was carried out for compounds 5 b, 5j, 5n and 5o . (Approved by HU-IACUC) 52 (Pages S34 and S35, supplementary file ).…”

Section: Methodsmentioning

confidence: 99%

Rational design of biodegradable sulphonamide candidates treating septicaemia by synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme

El-Dershaby

El-Hawash

Kassab

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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A new series of co-drugs was designed based on hybridising the dihydropteroate synthase (DHPS) inhibitor sulphonamide scaffold with the COX-2 inhibitor salicylamide pharmacophore through biodegradable linkage to achieve compounds with synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme to enhance antibacterial activity for treatment of septicaemia. Compounds 5 b, 5j, 5n and 5o demonstrated potent in vitro COX-2 inhibitory activity comparable to celecoxib. 5j and 5o exhibited ED 50 lower than celecoxib in carrageenan-induced paw edoema test with % PGE2 inhibition higher than celecoxib. Furthermore, 5 b , 5j and 5n showed gastric safety profile like celecoxib. Moreover, in vivo antibacterial screening revealed that, 5j showed activity against S.aureus and E.coli higher than sulfasalazine. While, 5o revealed activity against E.coli higher than sulfasalazine and against S.aureus comparable to sulfasalazine. Compound 5j achieved the target goal as potent inhibitor of COX-2/PGE2 axis and in vivo broad-spectrum antibacterial activity against induced septicaemia in mice.

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Design and synthesis of pyrimidine-5-carbonitrile hybrids as COX-2 inhibitors: Anti-inflammatory activity, ulcerogenic liability, histopathological and docking studies

Cited by 39 publications

References 44 publications

Drug Discovery of New Anti-Inflammatory Compounds by Targeting Cyclooxygenases

Drug Discovery of New Anti-Inflammatory Compounds by Targeting Cyclooxygenases

Small molecule compounds with good anti-inflammatory activity reported in the literature from 01/2009 to 05/2021: a review

Rational design of biodegradable sulphonamide candidates treating septicaemia by synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme

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