Design, synthesis, biological evaluation and docking study of novel indole-2-amide as anti-inflammatory agents with dual inhibition of COX and 5-LOX

Huang, Yuanzheng; Zhang, Bin; Li, Jiaming; Liu, Huicai; Zhang, Yanchun; Zhang, Yang; Liu, Wandong

doi:10.1016/j.ejmech.2019.07.004

Cited by 60 publications

(27 citation statements)

References 28 publications

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“…With this aim, darbufelone and licofelone were first designed and clinically used as a dual COX/5-LOX inhibitory anti-inflammatory drugs. However, due to the high toxicity and/or limited efficacy, they were unable to be marketed 17,18 , making the development and bioactivity studies of dual inhibitors are still in urgent need. As it is noted that natural products and their semi-synthetic derivatives are potentially safer and more active than the synthetic compounds 19,20 , the metabolites from natural sources are extensively screened for their dual inhibitor properties.…”

Section: -Lipoxygenase (5-lox)mentioning

confidence: 99%

“…The five metabolites (1-5) were tested against 5-LOX (human recombinant) using 5-LOX assay kit (No. 437996, Sigma Aldrich) 17 . To 90 µl of 5-LOX enzyme solution added different test sample concentrations, 100 µl of de chromogen, and finally added 10 µl of the substrate (arachidonic acid) and gently shake or 10 min and absorbance was measured at 490 nm against the blank.…”

Section: -Lipoxygenase Inhibitory Assaymentioning

confidence: 99%

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Dual COX and 5-LOX inhibition by clerodane diterpenes from seeds of Polyalthia longifolia (Sonn.) Thwaites

Nguyen

Chandi

et al. 2020

Sci Rep

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Natural metabolites with their specific bioactivities are being considered as a potential source of materials for pharmacological studies. In this study, we successfully isolated and identified five known clerodane diterpenes, namely 16-oxo-cleroda-3,13(14)E-dien-15-oic acid (1), 16-hydroxy-cleroda-3,13-dien-15-oic acid (2), 16-hydroxy-cleroda-4(18),13-dien-16,15-olide (3), 3α,16α-dihydroxy-cleroda-4(18),13(14)Z-dien-15,16-olide (4), and 16α-hydroxy-cleroda-3,13(14)Z-dien-15,16-olide (5) from the methanolic extract of seeds of Polyalthia longifolia. Initially, all the isolated metabolites were investigated for COX-1, COX-2, and 5-LOX inhibitory activities using the standard inhibitory kits. Of which, compounds 3, 4, and 5 exhibited to be potent COX-1, COX-2, and 5-LOX inhibitors with the IC50 values similar or lower to those of the reference drugs. To understand the underlying mechanism, these compounds were subjected to molecular docking on COX-1, COX-2, and 5-LOX proteins. Interestingly, the in silico study results were in high accordance with in vitro studies where compounds 3, 4, and 5 hits assumed interactions and binding pattern comparable to that of reference drugs (indomethacin and diclofenac), as a co-crystallized ligand explaining their remarkable dual (COX/LOX) inhibitor actions. Taken together, our findings demonstrated that compounds 3, 4, and 5 functioned as dual inhibitors of COX/5-LOX and can contribute to the development of novel, more effective anti-inflammatory drugs with minimal side-effects.

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Section: -Lipoxygenase (5-lox)mentioning

confidence: 99%

Section: -Lipoxygenase Inhibitory Assaymentioning

confidence: 99%

Dual COX and 5-LOX inhibition by clerodane diterpenes from seeds of Polyalthia longifolia (Sonn.) Thwaites

Nguyen

Chandi

et al. 2020

Sci Rep

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“…The docking was performed by Autodock 4.2 with Lamarckian genetic algorithm to sift the best ligand‐receptor interaction. [ 98,99 ] Finally, graphical representations were completed by PyMOL. [ 100 ]…”

Section: Molecular Docking Of Quinones With Nlrp3mentioning

confidence: 99%

Quinones as preventive agents in Alzheimer’s diseases: focus on NLRP3 inflammasomes

Chen

Gao

Peng

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives Alzheimer's disease (AD) is a hidden neurological degenerative disease, which main clinical manifestations are cognitive dysfunction, memory impairment and mental disorders. Neuroinflammation is considered as a basic response of the central nervous system. NLRP3 (Nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3) inflammasome is closely related to the occurrence of neuroinflammation. Activation of the NLRP3 inflammasome results in the release of cytokines, pore formation and ultimately pyroptosis, which has demonstrated one of the critical roles in AD pathogenesis. Inhibition of the activity of NLRP3 is one of the focuses of the research. Therefore, NLRP3 represents an attractive pharmacological target, and discovery compounds with good NLRP3 inhibitory activity are particularly important. Key findings Quinones have good neuroprotective effects and prevent AD, which may be related to their regulation of inflammatory response. The molecular docking was used to explore 12 quinones with AD prevention and treatment and NLRP3. Docking results showed that the combination of anthraquinones and NLRP3 were the best, and the top two chemical compounds were Purpurin and Rhein, which are the most promising NLRP3 inhibitors. Summary These quinones may provide the theoretical basis for finding lead compounds for novel neuroprotective agents. Quinones as NLRP3 inflammasomes inhibitors Da-bao Chen et al.

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“…Compounds 4a – 4l , 5a – 5b , 6a – 6f , 7a – 7c were assessed for toxicity against RAW264.7 cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay [26]. The cytotoxicity tests were performed at the concentration of 40 μM and the results are shown in Table 2.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis and Investigation of the Potential Anti-Inflammatory Activity of 7-O-Amide Hesperetin Derivatives

et al. 2019

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To develop new anti-inflammatory agents, a series of 7-O-amide hesperetin derivatives was designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. All compounds showed inhibitory effect on LPS-induced NO production. Among them, 7-O-(2-(Propylamino)-2-oxoethyl)hesperetin (4d) and 7-O-(2-(Cyclopentylamino)-2-oxoethyl)hesperetin (4k) with hydrophobic side chains exhibited the most potent NO inhibitory activity (IC50 = 19.32 and 16.63 μM, respectively), showing stronger inhibitory effect on the production of pro- inflammatory cytokines tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) than indomethacin and celecoxib at 10 μM. The structure-activity relationships (SARs) suggested that the 7-O-amide unit was buried in a medium-sized hydrophobic cavity of the bound receptor. Furthermore, compound 4d could also significantly suppress the expression of inducible nitric oxide synthase enzymes (iNOS) and cyclooxygenase-2 (COX-2), through the nuclear factor-kappa B (NF-κB) signaling pathway.

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Design, synthesis, biological evaluation and docking study of novel indole-2-amide as anti-inflammatory agents with dual inhibition of COX and 5-LOX

Cited by 60 publications

References 28 publications

Dual COX and 5-LOX inhibition by clerodane diterpenes from seeds of Polyalthia longifolia (Sonn.) Thwaites

Dual COX and 5-LOX inhibition by clerodane diterpenes from seeds of Polyalthia longifolia (Sonn.) Thwaites

Quinones as preventive agents in Alzheimer’s diseases: focus on NLRP3 inflammasomes

Design, Synthesis and Investigation of the Potential Anti-Inflammatory Activity of 7-O-Amide Hesperetin Derivatives

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