Novel 1,2,4-triazine-quinoline hybrids: The privileged scaffolds as potent multi-target inhibitors of LPS-induced inflammatory response via dual COX-2 and 15-LOX inhibition

Ghanim, Amany M.; Rezq, Samar; Ibrahim, Tarek S.; Romero, Damián G.; Kothayer, Hend

doi:10.1016/j.ejmech.2021.113457

Cited by 31 publications

(9 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The common pharmacophoric structural features of the previously reported dual COX-2/15-LOX inhibitors include three regions: nitrogen-containing bicyclic ring, a central five or six-membered nitrogen-containing heterocycle (azole or azine), and a hydrophobic terminal usually containing an aromatic ring. Replacement of the central azole or azine with an open ring analogue has also been reported as observed in compounds ( J–M ) 16 .…”

Section: Introductionmentioning

confidence: 65%

“…Dual COX-2/LOX inhibitors, targeting eicosanoids for anticancer effects, showed superior anticancer activities to their single pathway counterpart inhibitors. This could be because inhibiting only the COX-2 arm increases AA availability and shifts the AA metabolic machinery towards excessive production of downstream LOX inflammatory mediators 11 , 16 . Furthermore, the combination therapy of licofelone (a dual COX/LOX inhibitor) with gefitinib (EGFR TKI) showed significant tumour growth inhibition in pancreatic cancer (PC) at a dose lower than doses of the individual agents 4 , 17 , 18 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Triple targeting of mutant EGFR ^L858R/T790M , COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation

Kothayer

Rezq

Abdelkhalek

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

We designed and synthesised novel quinazolinone tethered phenyl urea derivatives ( 6a–p ) that triple target the double mutant EGFR L858R/T790M , COX-2, and 15-LOX. Compounds ( 6e , 6d , 6j , 6m , and 6n ) not only had low micromolar IC50 inhibitory activities against the three targets, but they also showed good selectivity for COX-2 over COX-1 and for EGFR L858R/T790M over wild-type EGFR. Except for 6e and 6n , all of the tested compounds inhibited the NO production significantly more potently than celecoxib, diclofenac, and indomethacin. Compounds 6i and 6k reduced ROS levels more effectively than celecoxib and diclofenac. In terms of inhibiting TNF-α production, 6o- treated cells showed TNF-α level, which is ∼10 times lower than celecoxib. Furthermore, 6e and 6j had the highest anticancer activity against the breast cancer cell line BT-459 with growth inhibition percentages of 67.14 and 70.07%, respectively. Docking studies confirm their favoured binding affinity. The proposed compounds could be promising multi-targeted leads.

show abstract

Section: Introductionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Triple targeting of mutant EGFR ^L858R/T790M , COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation

Kothayer

Rezq

Abdelkhalek

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…This extra pocket is bordered by Tyr355, His90, Gln192, and Arg513 (the last residue is altered in COX-1 by His513). The high selective COX-2 inhibitors usually bind to Arg513 through the sulphone of their sulphonamide groups 13 , 59 . The docking results for the selected compounds showed better scoring within COX-2 active site (−8.54 to −6.26) than that within the COX-1 active site (-6.42 to −2.06).…”

Section: Resultsmentioning

confidence: 99%

Design and synthesis of novel quinazolinones conjugated ibuprofen, indole acetamide, or thioacetohydrazide as selective COX-2 inhibitors: anti-inflammatory, analgesic and anticancer activities

Sakr

Rezq

Ibrahim

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

Novel quinazolinones conjugated with indole acetamide (4a–c) , ibuprofen ( 7a–e), or thioacetohydrazide ( 13a,b, and 14a-d ) were designed to increase COX-2 selectivity. The three synthesised series exhibited superior COX-2 selectivity compared with the previously reported quinazolinones and their NSAID analogue and had equipotent COX-2 selectivity as celecoxib. Compared with celecoxib, 4 b , 7c , and 13 b showed similar anti-inflammatory activity in vivo , while 13 b and 14a showed superior inhibition of the inflammatory mediator nitric oxide, and 7 showed greater antioxidant potential in macrophages cells. Moreover, all selected compounds showed improved analgesic activity and 13 b completely abolished the pain response. Additionally, compound 4a showed anticancer activity in tested cell lines HCT116, HT29, and HCA7. Docking results were consistent with COX-1/2 enzyme assay results. In silico studies suggest their high oral bioavailability. The overall findings for compounds ( 4a,b, 7c, 13 b, and 14c ) support their potential role as anti-inflammatory agents.

show abstract

“…1,2,4-Triazine-quinoline and benzimidazole–thiazole hybrids have shown a dual COX-2/15-LOX inhibition being better than celecoxib and quercetin in acting on COX-2 and 15-LOX, respectively. The best compound found for 1,2,4-triazine–quinoline was 48 ( Figure 4 ), presenting IC 50 values of 0.047 µM (COX-2) and 1.81 µM (15-LOX) [ 110 ]; the best benzimidazole–thiazole hybrid was 49 ( Figure 4 ), with an IC 50 of 0.045 µM for COX-2 and 1.67 µM for 15-LOX [ 111 ].…”

Section: Multitarget Drugsmentioning

confidence: 99%

The Role of Organic Small Molecules in Pain Management

Cuesta

Meneses

2021

Molecules

View full text Add to dashboard Cite

In this review, a timeline starting at the willow bark and ending in the latest discoveries of analgesic and anti-inflammatory drugs will be discussed. Furthermore, the chemical features of the different small organic molecules that have been used in pain management will be studied. Then, the mechanism of different types of pain will be assessed, including neuropathic pain, inflammatory pain, and the relationship found between oxidative stress and pain. This will include obtaining insights into the cyclooxygenase action mechanism of nonsteroidal anti-inflammatory drugs (NSAID) such as ibuprofen and etoricoxib and the structural difference between the two cyclooxygenase isoforms leading to a selective inhibition, the action mechanism of pregabalin and its use in chronic neuropathic pain, new theories and studies on the analgesic action mechanism of paracetamol and how changes in its structure can lead to better characteristics of this drug, and cannabinoid action mechanism in managing pain through a cannabinoid receptor mechanism. Finally, an overview of the different approaches science is taking to develop more efficient molecules for pain treatment will be presented.

show abstract

Novel 1,2,4-triazine-quinoline hybrids: The privileged scaffolds as potent multi-target inhibitors of LPS-induced inflammatory response via dual COX-2 and 15-LOX inhibition

Cited by 31 publications

References 53 publications

Triple targeting of mutant EGFR ^L858R/T790M , COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation

Triple targeting of mutant EGFR ^L858R/T790M , COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation

Design and synthesis of novel quinazolinones conjugated ibuprofen, indole acetamide, or thioacetohydrazide as selective COX-2 inhibitors: anti-inflammatory, analgesic and anticancer activities

The Role of Organic Small Molecules in Pain Management

Contact Info

Product

Resources

About

Novel 1,2,4-triazine-quinoline hybrids: The privileged scaffolds as potent multi-target inhibitors of LPS-induced inflammatory response via dual COX-2 and 15-LOX inhibition

Cited by 31 publications

References 53 publications

Triple targeting of mutant EGFR L858R/T790M , COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation

Triple targeting of mutant EGFR L858R/T790M , COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation

Design and synthesis of novel quinazolinones conjugated ibuprofen, indole acetamide, or thioacetohydrazide as selective COX-2 inhibitors: anti-inflammatory, analgesic and anticancer activities

The Role of Organic Small Molecules in Pain Management

Contact Info

Product

Resources

About

Triple targeting of mutant EGFR ^L858R/T790M , COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation

Triple targeting of mutant EGFR ^L858R/T790M , COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation