Synthesis and biological evaluation of pyridazinone derivatives as selective COX-2 inhibitors and potential anti-inflammatory agents

Ahmed, Eman M.; Kassab, Asmaa E.; El‐Malah, Afaf; Hassan, Marwa S.A.

doi:10.1016/j.ejmech.2019.03.036

Cited by 49 publications

(46 citation statements)

References 22 publications

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“…When looking for medicines for Alzheimer's disease, nowadays, special attention is paid to nonsteroidal anti-inflammatory drugs (NSAIDs) [22]. The mechanism of NSAIDs may exert a protective effect on neuronal cells by inhibiting cyclooxygenase (COX) activity, especially COX-2, whose expression is strongly induced by inflammatory signals [19]. Several papers describe a relationship between long-term use of NSAIDs and a reduced risk of cognitive impairment, as well as a slower decline in cognitive function [18,30].…”

Section: Discussionmentioning

confidence: 99%

“…From another study of ours, we know that the tested compounds are selective COX-2 inhibitors [23]. Other researchers have also indicated the selective COX-2 activity of many pyridazinone derivatives [19]. Based on the literature data, one can attempt to explain the possible mechanisms of action of the derivatives studied.…”

Section: Discussionmentioning

confidence: 99%

“…The characteristic signal in the 1 H NMR spectrum near δ 4.98-5.10 ppm and the peak at around δ 70.01-70.42 ppm in the 13 C NMR spectrum indicate the presence of the methylene link that is typical for Mannich bases. According to many studies, the presence of an arylpiperazinyl or arylpiperidinyl group can significantly potentiate the analgesic activity of compound [19,[26][27][28][29]. Thereby, in our investigations, different amines were deliberately chosen to evaluate the influence of this pharmacophore on biological activity.…”

Section: Chemistrymentioning

confidence: 99%

“…inhibition of the COX-2 enzyme [19]. We have tested in our previous study some newly synthesized pyridazinone derivatives for their preferential inhibition of COX-2 over COX-1 [23], and on this basis, the four compounds were selected for further study on their effects on neuronal cell viability and neuronal properties.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Novel Pyrrolo[3,4-d]pyridazinone Derivatives on Lipopolysaccharide-Induced Neuroinflammation

Wakulik

Wiatrak

Szczukowski

et al. 2020

IJMS

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Neuroinflammation is considered to be one of the potential causes for the development of neurodegenerative diseases, including Alzheimer's disease. In this study, we evaluated the effect of four newly synthesized pyrrolo [3,4-d]pyridazinone derivatives on the neuron-like PC12 cells under simulated inflammation conditions by preincubation with lipopolysaccharide (LPS). Our novel derivatives are selective cyclooxygenase-2 (COX-2) inhibitors and have similar effects to nonsteroidal anti-inflammatory drugs (NSAIDs). We assessed viability (LDH assay), metabolic activity (MTT assay), DNA damage (number of double-strand breaks measured by fast halo assay), and the neuronal features of cells (average neurite length and neurite outgrowth measured spectrofluorimetrically). DCF-DA and Griess assays were also performed, which allowed determining the impact of the tested compounds on the level of oxygen free radicals and nitrites. LPS administration significantly negatively affected the results in all tests performed, and treatment with the tested derivatives in most cases significantly reduced this negative impact. Multiple-criteria decision analysis indicated that overall, the best results were observed for compounds 2a and 2b at a concentration of 10 µM. The new derivatives showed intense activity against free oxygen radicals and nitrites. Reduced reactive oxygen species level also correlated with a decrease in the number of DNA damage. The compounds improved neuronal features, such as neurite length and outgrowth, and they also increased cell viability and mitochondrial activity. Our results suggest that derivatives 2a and 2b may also act additionally on mechanisms other than 3a and 3b.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effect of Novel Pyrrolo[3,4-d]pyridazinone Derivatives on Lipopolysaccharide-Induced Neuroinflammation

Wakulik

Wiatrak

Szczukowski

et al. 2020

IJMS

View full text Add to dashboard Cite

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“…Adult male albino rats of Sprague Dawley strain weighing 130–150 g [ 40,41 ] were kept in the animal house unit of the pharmacology and toxicology department for a least 1 week before the experiments under standard conditions of light and temperature. All animals were accessed to standard laboratory diet consisting of vitamin mixture (1%), mineral mixture (4%), corn oil (10%), sucrose (20%), cellulose (0.2%), casein 95% pure (10.5%), and starch (54.3%).…”

Section: Methodsmentioning

confidence: 99%

Synthesis and biological evaluation of pyrazolone analogues as potential anti‐inflammatory agents targeting cyclooxygenases and 5‐lipoxygenase

Shabaan

Kamal

Faggal

et al. 2020

Archiv der Pharmazie

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New pyrazolone derivatives structurally related to celecoxib and FPL 62064 were synthesized and biologically evaluated for their inhibitory activity against cyclooxygenases (COXs) and 5‐lipoxygenase (5‐LOX) and their selectivity indices were calculated. The results showed that compounds 3f, 3h, 3l, and 3p have an excellent COX‐2 selectivity index. Moreover, they showed potent 5‐LOX inhibitory activity relative to celecoxib and zileuton, as positive controls. These promising candidates were further investigated for anti‐inflammatory activity using the carrageenan‐induced rat paw edema method and ulcerogenic liability. The results showed no ulceration, which implies their gastric safety profile. Moreover, these compounds were evaluated for prostaglandin (PGE2) production in rat serum. Molecular docking in the COX‐2 and 5‐LOX active sites was performed to rationalize their anti‐inflammatory activities. Strong binding interactions and effective docking scores were identified. The results indicated that these derivatives are good leads for dual‐acting COX‐2/5‐LOX inhibitors to be used as potent and safe anti‐inflammatory agents.

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Design, synthesis, and biological evaluation of new pyrazoloquinazoline derivatives as dual COX‐2/5‐LOX inhibitors

Shaaban

Kamal

Faggal

et al. 2020

Archiv der Pharmazie

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A new series of pyrazoloquinazoline derivatives equipped with different chalcones was designed, synthesized, and identified through 1 H nuclear magnetic resonance (NMR), 13 C NMR, and infrared spectroscopic techniques. Our design strategy of the quinazolinone-privileged scaffold as a new scaffold was based on merging pharmacophores previously reported to exhibit cyclooxygenase-2 (COX-2)/5lipoxygenase (5-LOX) inhibitory activity. All the newly synthesized derivatives were biologically evaluated for COX and 5-LOX inhibitory activity and COX-2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising antiinflammatory activity. Compound 3j was found to be the most promising derivative, with IC 50 values of 667 and 47 nM against COX-1 and COX-2, respectively, which are superior to that of celecoxib (IC 50 value against COX-2 = 95 nM), showing an SI of 14.2 that was much better than celecoxib. Compounds 3f and 3h exhibited COX-1 inhibition, with IC 50 values of 1,485 and 684 nM, respectively. The synthesized compounds showed a significant inhibitory activity against 5-LOX, with IC 50 values ranging from 0.6 to 4.3 µM, where compounds 3f and 3h were found to be the most potent derivatives, with IC 50 values of 0.6 and 1.0 µM, respectively, in comparison with that of zileuton (IC 50 = 0.8 µM). These promising derivatives, 3f, 3h, and 3j, were further investigated in vivo for anti-inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX-2 and 5-LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX-2 and 5-LOX as dual inhibitors, as a new avenue in anti-inflammatory therapy.

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Synthesis and biological evaluation of pyridazinone derivatives as selective COX-2 inhibitors and potential anti-inflammatory agents

Cited by 49 publications

References 22 publications

Effect of Novel Pyrrolo[3,4-d]pyridazinone Derivatives on Lipopolysaccharide-Induced Neuroinflammation

Effect of Novel Pyrrolo[3,4-d]pyridazinone Derivatives on Lipopolysaccharide-Induced Neuroinflammation

Synthesis and biological evaluation of pyrazolone analogues as potential anti‐inflammatory agents targeting cyclooxygenases and 5‐lipoxygenase

Design, synthesis, and biological evaluation of new pyrazoloquinazoline derivatives as dual COX‐2/5‐LOX inhibitors

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