Febuxostat-based amides and some derived heterocycles targeting xanthine oxidase and COX inhibition. Synthesis, in vitro and in vivo biological evaluation, molecular modeling and in silico ADMET studies

Rashad, Aya Y; Kassab, Shaymaa E.; Daabees, Hoda G.; Moneim, Ahmed E. Abdel; Rostom, Sherif A. F.

doi:10.1016/j.bioorg.2021.104948

Cited by 18 publications

(13 citation statements)

References 63 publications

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“…Previously study reported that 3‐methylxanthine produced xanthine and uric acid during oxidation, suggesting that 3‐methylxanthine may also be involved in the pathogenesis of gout through purine metabolism 32 . Significantly, most of the previous studies reported that piperine and ibuprofen have anti‐inflammatory effects 33–35 . Some experiments have proved that piperine can inhibit the inflammation induced by the crystallization of monosodium urate 36 .…”

Section: Discussionmentioning

confidence: 99%

“…32 Significantly, most of the previous studies reported that piperine and ibuprofen have anti-inflammatory effects. [33][34][35] Some experiments have proved that piperine can inhibit the inflammation induced by the crystallization of monosodium urate. 36 A previous study also found that ibuprofen can inhibit the activity of xanthine oxidase and reduce the occurrence of inflammation.…”

Section: Adverse Effects Of Metabolites On Goutmentioning

confidence: 99%

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Assessing the causal association between human blood metabolites and the risk of gout

Xie,

Li,

Zhang

et al. 2023

Eur J Clin Investigation

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BackgroundThe occurrence of gout is closely related to metabolism, but there is still a lack of evidence on the causal role of metabolites in promoting or preventing gout.MethodsWe applied a two‐sample Mendelian randomization (MR) analysis to assess the association between 486 serum metabolites and gout using genome‐wide association study statistics. The inverse variance weighting method was used to generate the main results, while sensitivity analyses using MR‐Egger, weighted median, Cochran's Q test, Egger intercept test, and leave‐one‐out analysis, were performed to assess the stability and reliability of the results. We also performed a metabolic pathway analysis to identify potential metabolic pathways.ResultsAfter screening, 486 metabolites were retained for MR analysis. After screening by IVW and sensitivity analysis, 14 metabolites were identified with causal effect on gout (P < 0.05), among which hexadecanedioate was the most significant candidate metabolite associated with a lower risk of gout (IVW OR = 0.50; 95% CI = 0.38–0.67; P = 1.65 × 10−6). Metabolic pathway analysis identified one pathway that may be associated with the disease.ConclusionThis MR study combining genomics with metabolomics provides a novel insight into the causal role of blood metabolites in the risk of gout, which implies that examination of certain blood metabolites would be a feasible strategy for screening populations with a higher risk of gout.

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Section: Discussionmentioning

confidence: 99%

Section: Adverse Effects Of Metabolites On Goutmentioning

confidence: 99%

Assessing the causal association between human blood metabolites and the risk of gout

Xie,

Li,

Zhang

et al. 2023

Eur J Clin Investigation

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“…Molecular docking studies were carried out using Molecular Operating Environment (MOE 2014.0901) software, Chemical Computing Group, Montreal, Canada, following the docking protocol [ 36 ]. The X-ray crystal structure of the TGF-β (PDB ID: 1VJY) active site was downloaded from the RCSB Protein Date Bank website [ 37 ].…”

Section: Methodsmentioning

confidence: 99%

The Role of Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitors in The Attenuation of CCl4-Induced Liver Fibrosis in Rats

et al. 2023

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Liver Fibrosis can be life-threatening if left untreated as it may lead to serious, incurable complications. The common therapeutic approach is to reverse the fibrosis while the intervention is still applicable. Celecoxib was shown to exhibit some antifibrotic properties in the induced fibrotic liver in rats. The present study aimed to investigate the possible antifibrotic properties in CCl4-induced liver fibrosis in male Sprague–Dawley rats compared to celecoxib of three novel methoxylated pyrazolo[3,4-d]pyrimidines. The three newly synthesized compounds were proved to be safe candidates. They showed a therapeutic effect against severe CCl4-induced fibrosis but at different degrees. The three compounds were able to partially reverse hepatic architectural distortion and reduce the fibrotic severity by showing antioxidant properties reducing MDA with increasing GSH and SOD levels, remodeling the extracellular matrix proteins and liver enzymes balance, and reducing the level of proinflammatory (TNF-α and IL-6) and profibrogenic (TGF-β) cytokines. The results revealed that the dimethoxy-analog exhibited the greatest activity in all the previously mentioned parameters compared to celecoxib and the other two analogs which could be attributed to the different methoxylation patterns of the derivatives. Collectively, the dimethoxy-derivative could be considered a safe promising antifibrotic candidate.

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“…All the synthesised target compounds were screened for their COX-1 and COX-2 inhibitory activities according to the previously reported methods 49 , 50 (page S34, 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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Febuxostat-based amides and some derived heterocycles targeting xanthine oxidase and COX inhibition. Synthesis, in vitro and in vivo biological evaluation, molecular modeling and in silico ADMET studies

Cited by 18 publications

References 63 publications

Assessing the causal association between human blood metabolites and the risk of gout

Assessing the causal association between human blood metabolites and the risk of gout

The Role of Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitors in The Attenuation of CCl4-Induced Liver Fibrosis in Rats

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

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