Novel tetrazole-based selective COX-2 inhibitors: Design, synthesis, anti-inflammatory activity, evaluation of PGE2, TNF-α, IL-6 and histopathological study

Background: The reported binding mode of ibuprofen in the COX-2 binding site indicated that the carboxylic group binds with Arg-120 and Tyr-355 at the entrance of the cyclooxygenase channel and does not extend into the pocket. This accounted for the non-selectivity of ibuprofen. Based on this fact, we assumed that extending the length of the carboxylic acid moiety in ibuprofen and adding more bulky rigid groups as well as bulky groups carrying H-bonding functions might increase the selectivity and reduce the side effects of ibuprofen while maintaining its analgesic and anti-inflammatory activities. Objective: In this work, four series of ibuprofen derivatives were designed and prepared. The compounds were designed by increasing the length of the carboxylate group along with the incorporation of large hydrophobic groups. Method: Four series of ibuprofen derivatives were synthesized starting from ibuprofen. Their chemical structure was confirmed by spectral data. All the compounds were tested for their COX inhibitory activity. Results : The best COX-2 activity and selectivity were obtained with compounds 5c and 5d, which were subjected to further in vivo testing (carrageenan-induced paw edema, rat serum PGE2, TNF- α and IL-6, hot plate latency test) to investigate their anti-inflammatory and analgesic activities as well as their effects on the gastric mucosa. The anti-inflammatory activity of both compounds was comparable to that of ibuprofen, diclofenac, and indomethacin. Both compounds suppressed the production of PGE2 as well as the rat serum concentrations of both TNF-α and IL-6. This potent anti-inflammatory and analgesic behavior was not accompanied by any effect on the gastric mucosa. Docking simulation studies of the two compounds explained the higher selectivity for the COX-2 enzyme. Conclusion: Potent and selective ibuprofen derivatives can be successively obtained by extending the length of the carboxylic acid moiety in ibuprofen and adding more bulky rigid groups as well as bulky groups with H-bonding functions.

Download Full-text

Design and synthesis of pyrimidine-5-carbonitrile hybrids as COX-2 inhibitors: Anti-inflammatory activity, ulcerogenic liability, histopathological and docking studies

Bioorganic Chemistry ◽

10.1016/j.bioorg.2020.104555 ◽

2020 ◽

pp. 104555

Author(s):

Abdallah M. Alfayomy ◽

Salah A. Abdel-Aziz ◽

Adel A. Marzouk ◽

Montaser Sh. A. Shaykoon ◽

Atsushi Narumi ◽

...

Keyword(s):

Docking Studies ◽

Inflammatory Activity ◽

Design And Synthesis ◽

Cox 2 ◽

Anti Inflammatory ◽

Cox 2 Inhibitors

Download Full-text

Design, Synthesis and Comprehensive Investigations of Pyrrolo[3,4-d]pyridazinone-Based 1,3,4-Oxadiazole as New Class of Selective COX-2 Inhibitors

International Journal of Molecular Sciences ◽

10.3390/ijms21249623 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9623

Author(s):

Łukasz Szczukowski ◽

Edward Krzyżak ◽

Adrianna Zborowska ◽

Patrycja Zając ◽

Katarzyna Potyrak ◽

...

Keyword(s):

Molecular Docking ◽

Docking Studies ◽

One Pot ◽

Design Synthesis ◽

Biological Studies ◽

Cox 2 ◽

Anti Inflammatory ◽

Dna Strand ◽

Cox 2 Inhibitors

The long-term use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in treatment of different chronic inflammatory disorders is strongly restricted by their serious gastrointestinal adverse effects. Therefore, there is still an urgent need to search for new, safe, and efficient anti-inflammatory agents. Previously, we have reported the Mannich base-type derivatives of pyrrolo[3,4-d]pyridazinone which strongly inhibit cyclooxygenase, have better affinity to COX-2 isoenzyme and exert promising anti-oxidant activity. These findings encouraged us to perform further optimization of that structure. Herein, we present the design, synthesis, molecular docking, spectroscopic, and biological studies of novel pyrrolo[3,4-d]pyridazinone derivatives bearing 4-aryl-1-(1-oxoethyl)piperazine pharmacophore 5a,b–6a,b. The new compounds were obtained via convenient, efficient, one-pot synthesis. According to in vitro evaluations, novel molecules exert no cytotoxicity and act as selective COX-2 inhibitors. These findings stay in good correlation with molecular modeling results, which additionally showed that investigated compounds take a position in the active site of COX-2 very similar to Meloxicam. Moreover, all derivatives reduce the increased level of reactive oxygen and nitrogen species and prevent DNA strand breaks caused by oxidative stress. Finally, performed spectroscopic and molecular docking studies demonstrated that new compound interactions with bovine serum albumin (BSA) are moderate, formation of complexes is in one-to-one ratio, and binding site II (subdomain IIIA) is favorable.

Download Full-text

New methyl 5-(halomethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates as selective COX-2 inhibitors and anti-inflammatory agents: Design, synthesis, biological evaluation, and docking study

Bioorganic Chemistry ◽

10.1016/j.bioorg.2020.104333 ◽

2020 ◽

Vol 104 ◽

pp. 104333

Author(s):

Sin-Min Li ◽

Shuo-En Tsai ◽

Chia-Yin Chiang ◽

Cheng-Yen Chung ◽

Tsung-Jui Chuang ◽

...

Keyword(s):

Docking Study ◽

Biological Evaluation ◽

Design Synthesis ◽

Cox 2 ◽

Anti Inflammatory ◽

Cox 2 Inhibitors

Download Full-text

The Acidic Fraction of Isatidis Radix Regulates Inflammatory Response in LPS-Stimulated RAW264.7 Macrophages through MAPKs and NF-κB Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/8879862 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Zhenyu Fan ◽

Liangliang Cai ◽

Yage Wang ◽

Qiuyan Zhu ◽

Shengnan Wang ◽

...

Keyword(s):

Sore Throat ◽

Mechanism Of Action ◽

Inflammatory Activity ◽

Enzyme Linked Immunosorbent Assay ◽

Dependent Manner ◽

Raw264.7 Macrophages ◽

Tnf Α ◽

Acidic Fraction ◽

Cox 2 ◽

Anti Inflammatory

Isatidis Radix, the dried root of Isatidis indigotica Fort, is a traditional heat-clearing and detoxicating herb, which has the antiviral and anti-inflammatory activity and immune regulation. It has been widely used to treat cold, fever, sore throat, mumps, and tonsillitis in clinics. A previous study demonstrated that the acidic fraction of Isatidis Radix (RIAF) had strong anti-inflammatory activity, but the mechanism of action was not well elucidated. Lipopolysaccharide- (LPS-) induced RAW264.7 cells were employed to observe the anti-inflammatory activity of RIAF. The level of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), nitric oxide (NO), prostaglandin E2 (PGE2), and interleukin-6 (IL-6) was determined by enzyme-linked immunosorbent assay kits. Western blot was performed to quantify the expression of extracellular signal-regulated kinase (ERK) 1/2, c-jun NH2-termianl kinase (JNK), p38, inducible NO synthetase (iNOS), cyclooxygenase (COX)-2, andnuclear factor-κB (NF-κB). Immunofluorescence assay and electrophoretic mobility shift assay (EMSA) were used to quantify the translocation and the binding-DNA activity of NF-κB. RIAF could inhibit the secretion of inflammatory cytokines (PGE2, IL-6, IL-1β, and NO, other than TNF-α) in a dose-dependent manner. Further investigation showed that the expression of iNOS and COX-2 induced by LPS were downregulated by treatment with RIAF. Meanwhile, data from the signal pathway exhibited that RIAF significantly suppressed the phosphorylation of ERK1/2, JNK, and p38 and reduced the translocation of NF-κB from the cytoplasm to nucleus, as well as the binding-DNA activity. The anti-inflammatory mechanism of action of RIAF was to reduce inflammation-associated gene expression (iNOS, COX-2, IL-1β, IL-6) by regulating the phosphorylation of the mitogen-activated protein kinases (MAPK) pathway and interventing the activation of the NF-κB pathway, which partly illustrated the basis of treatment of Isatidis Radix on cold, fever, sore throat, mumps, and tonsillitis in clinics.

Download Full-text