Quinone-containing compounds have risen as promising anti-inflammatory targets; however, very little research has been directed to investigate their potentials. Accordingly, the current study aimed to design and synthesize group of quinones bearing different substituents to investigate the effect of these functionalities on the anti-inflammatory activities of this important scaffold. The choice of these substituents was carefully done, varying from a directly attached heterocyclic ring to different aromatic moieties linked through a nitrogen spacer. Both in vitro and in vivo anti-inflammatory activities of the synthesized compounds were assessed relative to the positive standards: celecoxib and indomethacin. The in vitro enzymatic and transcription inhibitory actions of all the synthesized compounds were tested against cyclooxygenase-2 (COX-2), cyclooxygenase-1 (COX-1), and 5-lipoxygenase (LOX) and the in vivo gene expression of Interleukin-1, interleukin 10, and Tumor Necrosis Factor-α (TNF-α) were determined. The IC50 against COX-1 and COX-2 enzymes obtained by the immunoassay test revealed promising activities of sixteen compounds with selectivity indices higher than 100-fold COX-2 selectivity. Out of those, four compounds revealed selectivity indices comparable to celecoxib as a reference drug. Furthermore, all the tested compounds inhibited LOX with an IC50 in the range of 1.59-3.11 µM superior to that of the reference drug used; zileuton (IC50 = 3.50 µM). Consequently, these results highlight the promising LOX inhibitory activity of the tested compounds. The obtained in vivo paw edema results showed high inhibitory percentage for the compounds 9a, 9b, and 11a with the significant lower TNF-α relative mRNA expression for compounds 5a, 5d, 9a, 9b, 12d, and 12e. Finally, in silico docking of the most active compounds (5b, 5d, 9a, 9b) against COX2 enzymes presented an acceptable justification of the obtained in vitro inhibitory activities. As a conclusion, Compounds 5b, 5d, 9a, 9b, and 11b showed promising results and thus deserves further investigation.

Background: A dual COX/5-LOX strategy was adopted to develop new oxindole derivatives with superior anti-inflammatory activity. Methods: Three series of oxindoles - esters 4a-p, 6a-l and imines 7a-o - were synthesized and evaluated for their anti-inflammatory and analgesic activities. Molecular docking and predicted pharmacokinetic parameters were done for the most active compounds. A new LC-MS/MS method was developed and validated for the quantification of 4h in rat plasma. Results: Compounds 4h, 6d, 6f, 6j and 7m revealed % edema inhibition up to 100.00%; also, 4l and 7j showed 100.00% writhing protection. Compound 4h showed dual inhibitory activity with IC50 = 0.0533 and 0.4195 μM for COX-2 and 5-LOX, respectively. Molecular docking rationalized the obtained biological activity. The pharmacokinetic parameters of 4h from rat plasma were obtained.
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Cyclooxygenase 2 (COX-2) and 5-lipoxygenase (5-LOX) are overexpressed in gastric cancer cells, the dual inhibitors of which exhibit potential against metastasis and invasion with fewer side effects. To discover inhibitors targeting COX-2 and 5-LOX, we conducted ultrafiltration and enrichment calculation to screen candidates in quaternary alkaloids (QAs) from Zanthoxylum simulans through LC and LC-Q-TOF. For intensive peaks, peaks 19 (berberine) and 21 (chelerythrine) were observed as the most potent dual candidates and showed selective affinity to 5-LOX over COX-2. Peak 19 showed an enrichment at 4.36 for COX-2 and 22.81 for 5-LOX, while peak 21 showed an enrichment at 7.81 for COX-2 and 24.49 for 5-LOX. Molecular docking results revealed chelerythrine as a better dual inhibitor, showing time- and dose-dependent anti-proliferation against AGS cells. Bio-informatics strategies, such as Gene Expression Omnibus (GEO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG), suggested that hormone pathways in gastric cancer cells might be mediated by chelerythrine. Further reviews and summaries helped outline the mechanisms by which COX-2/5-LOX inhibitors might promote apoptosis in gastric cancer cells via estrogen, thyroid, and oxytocin signaling pathways. Chelerythrine was also added to gastric cancer cells to verify the regulation of these three signaling pathways. As a result, significant calling back of thyroid-stimulating hormone receptor (TSHR), thyroid hormone α3 (TRα3), and thyroid hormone receptor β1 (TRβ1) and suppressing estrogen receptor α36 (ER-α36)-Src could benefit the anti-proliferation of chelerythrine. However, it was disappointing that regulation of estrogen receptor α66 (ER-α66), estrogen receptor β (ER-β), and oxytocin receptor (OTR) contributed inversely negative effects on anti-gastric cancer cells. At present, the integrative study not only revealed chelerythrine as the most potent dual COX-2/5-LOX inhibitor from QAs but also generally highlighted that comprehensive regulation of the estrogen, thyroid, and oxytocin pathway should be noted once gastric cancer cells were treated with inflammatory inhibitors.

Fragment merging approach was applied for the design of thiazole/thiazolidinone clubbed pyrazoline derivatives 5a-e, 6a-c, 7 and 10a-d as dual COX-2 and 5-LOX inhibitors. Compounds 5a, 6a, and 6b were the most potent and COX-2 selective inhibitors (IC50= 0.03-0.06 μM, SI = 282.7-472.9) with high activity against 5-LOX (IC50 = 4.36-4.86 μM), while compounds 5b and 10a were active and selective 5-LOX inhibitors with IC50 = 2.43 and 1.58 μM, respectively. In vivo assay and histopathological examination for most active candidate 6a revealed significant decrease in inflammation with higher safety profile in comparison to standard drugs. Compound 6a exhibited the same orientation and binding interactions as the reference COX-2 and 5-LOX inhibitors (celecoxib and quercetin, respectively). Consequently, compound 6a has been identified as a potential lead for further optimization and the development of safe and effective anti-inflammatory drugs.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, known as coronavirus disease 2019 (COVID-19) causes cytokine release syndrome (CRS), leading to acute respiratory distress syndrome (ARDS), acute kidney and cardiac injury, liver dysfunction, and multiorgan failure. Although several studies have discussed the role of 5-lipoxygenase (5-LOX) in viral infections, such as influenzae and SARS, it remains unexplored in the pathophysiology of COVID-19. 5-LOX acts on free arachidonic acid (AA) to form proinflammatory leukotrienes (LTs). Of note, numerous cells involved with COVID-19 (e.g., inflammatory and smooth muscle cells, platelets, and vascular endothelium) widely express leukotriene receptors. Moreover, 5-LOX metabolites induce the release of cytokines (e.g., tumour necrosis factor-α [TNF-α], interleukin-1α [IL-1α], and interleukin-1β [IL-1β]) and express tissue factor on cell membranes and activate plasmin. Since macrophages, monocytes, neutrophils, and eosinophils can express lipoxygenases, activation of 5-LOX and the subsequent release of LTs may contribute to the severity of COVID-19. This review sheds light on the potential implications of 5-LOX in SARS-CoV-2-mediated infection and the anticipated therapeutic role of 5-LOX inhibitors.

Inflammation is strictly associated with cancer and plays a key role in tumor development and progression. Several epidemiological studies have demonstrated that inflammation can predispose to tumors, therefore targeting inflammation and the molecules involved in the inflammatory process could represent a good strategy for cancer prevention and therapy. In the past, several clinical studies have demonstrated that many anti-inflammatory agents, including non-steroidal anti-inflammatory drugs (NSAIDs), are able to interfere with the tumor microenvironment by reducing cell migration and increasing apoptosis and chemo-sensitivity. This review focuses on the link between inflammation and cancer by describing the anti-inflammatory agents used in cancer therapy, and their mechanisms of action, emphasizing the use of novel anti-inflammatory agents with significant anticancer activity.

Human 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds, 3a and 3b, exhibiting a potent inhibitory profile against 5-LOX with IC50 values less than 1 µmol/L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fused-ring system. Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX. In particular, compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity, but also significantly decreased infarct damage in a mouse model of cerebral ischemia. Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data. In conclusion, the excellent in vitro and in vivo inhibitory activities of these compounds against 5-LOX suggested that these novel chemical structures have a promising therapeutic potential to treat leukotriene-related disorders.

The indoles bearing a tosyl group at N-1 and a dipeptide substituent at C-3 were screened for anti-inflammatory and anti-hyperalgesic activities. Some of the compounds made significant reduction in the dextran induced swelling and capsaicin induced pain in the albino mice. About 95% reversal in capsaicin induced pain occurred in the presence of 5 mg kg(-1) of compound 7b, 7d and 7h while diclofenac showed 90% reversal when its 10 mg kg(-1) dose was used. In order to examine the mode of action of these compounds; COX-1, COX-2 and 5-LOX enzyme immunoassays were performed. The IC50 of compound 7b for COX-2 and 5-LOX were in the nM range: 5-LOX, IC50 = 2.0 nM; COX-2, IC50 = 6.3 nM, selectivity for COX-2 over COX-1 was 351. The interactions of the compounds with COX-2 and 5-LOX were supported by the physical parameters including Ki, Ka and ΔG. The most potent compounds 7b, 7d and 7h showed no toxicity to the animals and were identified as the promising leads for anti-inflammatory drugs.