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New pyrazolo[3,4-d]pyrimidine derivatives 7a-h and 8a-h were synthesized and evaluated for their in vitro inhibitory potential against COX-1, COX-2, 5-LOX along with the NO release inhibitory activity to assess their anti-inflammatory potential. Most compounds confered inhibitory activity at a micromolar level and exhibited prominent selectivity towards COX-2 especially in the 8a-h series. The most useful compound 8e as a COX-2/5-LOX dual inhibitor, exhibited IC 50 results of; 1.837 µM for COX-2, 2.662 µM for 5-LOX with an acceptable NO release inhibition rate of 66.02 %. Compounds 7e, 7f, 8e and 8f proved their efficiency as 5-LOX/NO release dual inhibitors; with IC 50 values of 2.833, 1.952, 2.662 and 1.573 µM, respectively for 5-LOX biotarget, and with superior NO inhibitory ratio of 73.85, 65.57, 66.02 and 72.28 %, respectively. The in vivo anti-inflammatory assay explored that 7e is the most effective with minimal gastric ulceration prevalence. Molecular docking in the active site of both COX-2 and 5-LOX showed that, the most active 8e and 7e are correctly oriented inside the COX-2 binding pocket with unique binding mode independently on the reference celecoxib. Also, they demonstrated superior binding affinities to the 5-LOX enzyme over both the Zileuton as a reference drug and the normal ligand 30Z. The stability of the complex formed between the most promising candidates 7e or 8e with the COX-2 and 5-LOX active sites, was considered using a typical atomistic 100 ns dynamic simulation study. Investigation of the SAR revealed the importance of both the sulfonamide group in the 8a-h series and the substituents of the 3-phenyl ring tethered on the 1,2,4-oxadiazole core., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Aims: Ulcerative colitis (UC) is characterized by the up-regulation of pro-inflammatory mediators, apoptotic signals, and oxidative stress that can lead to an increased risk of colorectal cancer. The present study aims to investigate the possible role of myristicin in modulating endoplasmic reticulum stress (ERS) and risk-associated conditions in acetic acid (AA)-induced UC., Materials and Methods: Adult male rats were treated with 150 mg/kg body weight of myristicin or mesalazine orally either as pre/post treatment or post-treatment only. The gene expression of glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), and nuclear factor kappa B (NF-κB), percentage of DNA fragmentation, and serum levels of some oxidative and inflammatory markers were measured., Key Findings: The results indicated the potential upregulation of ERS, pro-apoptotic, lipid peroxidation, and pro-inflammatory cascades by induction of UC in rats. However, myristicin could effectively reverse the deteriorated effects of ulceration in colonic mucosa. It was mediated through downregulation of the ERS markers GRP78 and CHOP genes expression, reduction of NF-κB mRNA expression, DNA fragmentation, reduced lipid peroxidation, myeloperoxidase (MPO) activity and pro-inflammatory markers (Tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β) and cyclo‑oxygenase (COX-2) activity). Accompanied by elevated levels of IL-10, colonic Nuclear erythroid factor (Nrf-2) and Heme oxygenase (HO-1) activity as well as blood antioxidant enzymes activity. Results of docking might confirm the biological results of our study., Significance: Myristicin could effectively modulate important stress, and inflammatory effectors and protect mucosal DNA from oxidative damage which can serve as a promising candidate for the treatment of ulcerative colitis., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the author., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Uncontrolled inflammation predisposes to pleiotropic effects leading to cancer development thanks to promoting all stages of tumorigenesis. Therefore, cancer-associated inflammation has been delegated as the seventh hallmark of cancer. Thus, raging the war against both inflammation and cancer via the innovation of bioactive agents with dual anti-inflammatory and anticancer activities is a necessity. Herein, a novel series of pyrazole-chalcone analogs of Lonazolac (7a-g and 8a-g) have been synthesized and investigated for their in vitro anticancer activity against four cancer cell lines using the MTT assay method. Among all, hybrid 8g was the most potent against three cancer cell lines, HeLa, HCT-116, and RPMI-822 with IC 50 values of 2.41, 2.41, and 3.34 µM, respectively. In contrast, hybrid 8g showed moderate inhibitory activity against MCF-7 with IC 50 28.93 μM and with a selectivity profile against MCF-10A (non-cancer cells). Mechanistically, hybrid 8g was the most potent inhibitor against tubulin polymerization (IC 50  = 4.77 µM), suggesting tubulin as a molecular target and explaining the observed cytotoxicity of hybrid 8g. This was mirrored by the detected potent pre-G1 apoptosis induction and G2/M cell cycle arrest. Moreover, hybrid8gexhibited selectivity against COX-2 (IC 50  = 5.13 µM) more than COX-1 (IC 50  = 33.46 µM), indicating that 8g may have lower cardiovascular side effects, but is still not potent as celecoxib (COX-2 IC 50  = 0.204 µM, COX-1 = 35.8 µM). Notably, hybrid 8g showed promising inhibitory activity towards 5-LOX (IC 50  = 5.88 µM). Finally, the anti-inflammatory activity of hybrid8 g was confirmed by high iNOS and PGE2 inhibitory activities in LPS-stimulated RAW cells with IC 50 values of4.93 µM and 10.98 µM, respectively, that accompanied by showingthe most potent inhibition of NO release (70.61 % inhibition rate). Molecular docking studies of hybrid 8g confirmed good correlations with the executed biological results. Furthermore, hybrid 8g had good drug-likeness and suitable physicochemical properties. Taken together, the combined results suggested hybrid8gas a promising orally administered candidate in the journey of repurposing NSAIDs for cancer chemopreventionand treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)