Short-term celecoxib (celebrex) adjuvant therapy: a clinical trial study on COVID-19 patients.

BACKGROUND: It is known that severe acute respiratory coronavirus 2 (SARS-CoV-2) is the viral strain responsible for the recent coronavirus disease 2019 (COVID-19) pandemic. Current documents have demonstrated that the virus causes a PGE2 storm in a substantial proportion of patients via upregulating cyclooxygenase-2 (COX-2) and downregulating prostaglandin E2 (PGE2)-degrading enzymes within the host cell. AIM: Herein, we aimed to study how short-term treatment with celecoxib (Celebrex), a selective COX-2 inhibitor, affects demographic features, early symptoms, O2 saturation, and hematological indices of cases with COVID-19. METHODS: A total of 67 confirmed COVID-19 cases with a mild or moderate disease, who had been referred to an institutional hospital in south-eastern Iran from October 2020 to September 2021, were enrolled. Demographic characteristics, symptoms, and hematological indices of the patients were recorded within different time periods. One-way ANOVA or Kruskal-Wallis tests were used to determine differences between data sets based on normal data distribution. RESULTS: O2 saturation was statistically different between the control group and patients receiving celecoxib (p = 0.039). There was no marked difference between the groups in terms of the symptoms they experienced (p > 0.05). On the first days following Celebrex therapy, analysis of complete blood counts showed that white blood cell (WBC) counts were markedly lower in patients treated with a high dose of celecoxib (0.4 g/day) than in controls (p = 0.026). However, mean lymphocyte levels in patients receiving a high dose of celecoxib (0.4 g/day) were markedly higher than in patients receiving celecoxib with half of the dose (0.2 g/day) for one week or the untreated subjects (p = 0.004). Changes in platelet count also followed the WBC alteration pattern. CONCLUSION: Celecoxib is a relatively safe, inexpensive, and widely available drug with non-steroidal anti-inflammatory properties. The therapeutic efficacy of celecoxib depends on the administrated dose. Celecoxib might improve disease-free survival in patients with COVID-19.

Antiinflammation Derived Suzuki-Coupled Fenbufens as COX-2 Inhibitors: Minilibrary Construction and Bioassay.

A small fenbufen library comprising 18 compounds was prepared via Suzuki Miyara coupling. The five-step preparations deliver 9-17% biphenyl compounds in total yield. These fenbufen analogs exert insignificant activity against the IL-1 release as well as inhibiting cyclooxygenase 2 considerably. Both the para-amino and para-hydroxy mono substituents display the most substantial COX-2 inhibition, particularly the latter one showing a comparable activity as celecoxib. The most COX-2 selective and bioactive disubstituted compound encompasses one electron-withdrawing methyl and one electron-donating fluoro groups in one arene. COX-2 is selective but not COX-2 to bioactive compounds that contain both two electron-withdrawing groups; disubstituted analogs with both resonance-formable electron-donating dihydroxy groups display high COX-2 activity but inferior COX-2 selectivity. In silico simulation and modeling for three COX-2 active-p-fluoro, p-hydroxy and p-amino-fenbufens show a preferable docking to COX-2 than COX-1. The most stabilization by the p-hydroxy fenbufen with COX-2 predicted by theoretical simulation is consistent with its prominent COX-2 inhibition resulting from experiments.

EGFR and COX-2 Dual Inhibitor: The Design, Synthesis, and Biological Evaluation of Novel Chalcones.

For most researchers, discovering new anticancer drugs to avoid the adverse effects of current ones, to improve therapeutic benefits and to reduce resistance is essential. Because the COX-2 enzyme plays an important role in various types of cancer leading to malignancy enhancement, inhibition of apoptosis, and tumor-cell metastasis, an indispensable objective is to design new scaffolds or drugs that possess combined action or dual effect, such as kinase and COX-2 inhibition. The start compounds A1 to A6 were prepared through the diazo coupling of 3-aminoacetophenone with a corresponding phenol and then condensed with two new chalcone series, C7-18. The newly synthesized compounds were assessed against both COX-2 and epidermal growth factor receptor (EGFR) for their inhibitory effect. All novel compounds were screened for cytotoxicity against five cancer cell lines. Compounds C9 and G10 exhibited potent EGFR inhibition with IC50 values of 0.8 and 1.1 µM, respectively. Additionally, they also displayed great COX-2 inhibition with IC50 values of 1.27 and 1.88 µM, respectively. Furthermore, the target compounds were assessed for their cytotoxicity against pancreatic ductal cancer (Panc-1), lung cancer (H-460), human colon cancer (HT-29), human malignant melanoma (A375) and pancreatic cancer (PaCa-2) cell lines. Interestingly, compounds C10 and G12 exhibited the strongest cytotoxic effect against PaCa-2 with average IC50 values of 0.9 and 0.8 µM, respectively. To understand the possible binding modes of the compounds under investigation with the receptor cites of EGFR and COX-2, a virtual docking study was conducted.

Celecoxib Analogues for Cancer Treatment: An Update on OSU-03012 and 2,5-Dimethyl-Celecoxib.

Cyclooxygenase-2 (COX-2) is an important enzyme involved in prostaglandins biosynthesis from arachidonic acid. COX-2 is frequently overexpressed in human cancers and plays a major tumor promoting function. Accordingly, many efforts have been devoted to efficiently target the catalytic site of this enzyme in cancer cells, by using COX-2 specific inhibitors such as celecoxib. However, despite their potent anti-tumor properties, the myriad of detrimental effects associated to the chronic inhibition of COX-2 in healthy tissues, has considerably limited their use in clinic. In addition, increasing evidence indicate that these anti-cancerous properties are not strictly dependent on the inhibition of the catalytic site. These findings have led to the development of non-active COX-2 inhibitors analogues aiming at preserving the antitumor effects of COX-2 inhibitors without their side effects. Among them, two celecoxib derivatives, 2,5-Dimethyl-Celecoxib and OSU-03012, have been developed and suggested for the treatment of viral (e.g., recently SARS-CoV-2), inflammatory, metabolic diseases and cancers. These molecules display stronger anti-tumor properties than celecoxib and thus may represent promising anti-cancer molecules. In this review, we discuss the impact of these two analogues on cancerous processes but also their potential for cancer treatment alone or in combination with existing approaches.

Targeting cyclooxygenase enzyme for the adjuvant COVID-19 therapy.

Despite vigorous efforts, the COVID-19 pandemic continues to take a toll on the global health. The contemporary therapeutic regime focused on the viral spike proteins, viral 3CL protease enzyme, immunomodulation, inhibition of viral replication, and providing a symptomatic relief encouraged the repurposing of drugs to meet the urgency of treatment. Similarly, the representative drugs that proved beneficial to alleviate SARS-CoV-1, MERS-CoV, HIV, ZIKV, H1N1, and malarial infection in the past presented a sturdy candidature for ameliorating the COVID-19 therapeutic doctrine. However, most of the deliberations for developing effective pharmaceuticals proved inconsequential, thereby encouraging the identification of new pathways, and novel pharmaceuticals for capping the COVID-19 infection. The COVID-19 contagion encompasses a burst release of the cytokines that increase the severity of the infection mainly due to heightened immunopathogenicity. The pro-inflammatory metabolites, COX-2, cPLA2, and 5-LOX enzymes involved in their generation, and the substrates that instigate the origination of the innate inflammatory response therefore play an important role in intensifying and worsening of the tissue morbidity related to the coronavirus infection. The deployment of representative drugs for inhibiting these overexpressed immunogenic pathways in the tissues invaded by coronaviruses has been a matter of debate since the inception of the pandemic. The effectiveness of NSAIDs such as Aspirin, Indomethacin, Diclofenac, and Celecoxib in COVID-19 coagulopathy, discouraging the SARS viral replication, the inflammasome deactivation, and synergistic inhibition of H5N1 viral infection with representative antiviral drugs respectively, have provided a silver lining in adjuvant COVID-19 therapy. Since the anti-inflammatory NSAIDs and COXIBs mainly function by reversing the COX-2 overexpression to modulate the overproduction of pro-inflammatory cytokines and chemokines, these drugs present a robust treatment option for COVID-19 infection. This commentary succinctly highlights the various claims that support the status of immunomodulatory NSAIDs, and COXIBs in the adjuvant COVID-19 therapy.