Synthesis, biological evaluation, docking study and ulcerogenicity profiling of some novel quinoline-2-carboxamides as dual COXs/LOX inhibitors endowed with anti-inflammatory activity

Mostafa H. Abdelrahman, Bahaa G M Youssif, Mohamed A. abdelgawad, Ahmed H. Abdelazeem, Hussein M. Ibrahim, Abd El Ghany A Moustafa, Laurent Treamblu, Bukhari Syed Nasir Abbas

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

A series of novel quinoline-2-carboxamides 15–28 was synthesized and evaluated in vitro as dual COXs/LOX inhibitors. Compounds 19 and 27 exhibited the highest potency and selectivity for COX-2 inhibitory activity (IC50 = 1.21 and 1.13 μM, respectively; selectivity index (COX-1/COX-2) = 6.52 and 7.61, respectively) in comparison to the reference drug celecoxib (COX-2 IC50 = 0.88 μM; selectivity index (COX-1/COX-2) = 8.31). The anti-inflammatory activity of the newly synthesized compounds was further assessed in vivo using carrageenan induced paw edema assay. Interestingly, the in vitro results of COXs inhibitory assay were consistent with that of the in vivo assay where compounds 19 and 27 showed the highest anti-inflammatory activity with edema inhibition percentages of 59.38% and 65.03%, respectively compared to celecoxib (71.21%) after 5 h. Moreover, it was found that compounds 19 and 27 have a superior gastric safety profile comparable to indomethacin. The molecular docking study of compounds 19 and 27 into COX-2 active site suggested that these hits assumed binding pattern and interactions similar to that of bromocelecoxib (S-58) as a cocrystallized ligand explaining their remarkable COX-2 inhibitory activity and selectivity. Taken together, these results indicated that these derivatives are good leads for subsequent development into potential anti-inflammatory agents with least gastric damage.

Original languageEnglish
Pages (from-to)972-985
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume127
DOIs
Publication statusPublished - 15 Feb 2017
Externally publishedYes

Fingerprint

Celecoxib
Assays
Anti-Inflammatory Agents
Inhibitory Concentration 50
Edema
Stomach
Carrageenan
Indomethacin
Catalytic Domain
Ligands
Derivatives
Safety
Pharmaceutical Preparations
quinoline

Keywords

  • Anti-inflammatory
  • COXs
  • Docking
  • LOX
  • Quinoline-2-carboxamides

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Synthesis, biological evaluation, docking study and ulcerogenicity profiling of some novel quinoline-2-carboxamides as dual COXs/LOX inhibitors endowed with anti-inflammatory activity. / Abdelrahman, Mostafa H.; Youssif, Bahaa G M; abdelgawad, Mohamed A.; Abdelazeem, Ahmed H.; Ibrahim, Hussein M.; Moustafa, Abd El Ghany A; Treamblu, Laurent; Syed Nasir Abbas, Bukhari.

In: European Journal of Medicinal Chemistry, Vol. 127, 15.02.2017, p. 972-985.

Research output: Contribution to journalArticle

Abdelrahman, Mostafa H. ; Youssif, Bahaa G M ; abdelgawad, Mohamed A. ; Abdelazeem, Ahmed H. ; Ibrahim, Hussein M. ; Moustafa, Abd El Ghany A ; Treamblu, Laurent ; Syed Nasir Abbas, Bukhari. / Synthesis, biological evaluation, docking study and ulcerogenicity profiling of some novel quinoline-2-carboxamides as dual COXs/LOX inhibitors endowed with anti-inflammatory activity. In: European Journal of Medicinal Chemistry. 2017 ; Vol. 127. pp. 972-985.
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abstract = "A series of novel quinoline-2-carboxamides 15–28 was synthesized and evaluated in vitro as dual COXs/LOX inhibitors. Compounds 19 and 27 exhibited the highest potency and selectivity for COX-2 inhibitory activity (IC50 = 1.21 and 1.13 μM, respectively; selectivity index (COX-1/COX-2) = 6.52 and 7.61, respectively) in comparison to the reference drug celecoxib (COX-2 IC50 = 0.88 μM; selectivity index (COX-1/COX-2) = 8.31). The anti-inflammatory activity of the newly synthesized compounds was further assessed in vivo using carrageenan induced paw edema assay. Interestingly, the in vitro results of COXs inhibitory assay were consistent with that of the in vivo assay where compounds 19 and 27 showed the highest anti-inflammatory activity with edema inhibition percentages of 59.38{\%} and 65.03{\%}, respectively compared to celecoxib (71.21{\%}) after 5 h. Moreover, it was found that compounds 19 and 27 have a superior gastric safety profile comparable to indomethacin. The molecular docking study of compounds 19 and 27 into COX-2 active site suggested that these hits assumed binding pattern and interactions similar to that of bromocelecoxib (S-58) as a cocrystallized ligand explaining their remarkable COX-2 inhibitory activity and selectivity. Taken together, these results indicated that these derivatives are good leads for subsequent development into potential anti-inflammatory agents with least gastric damage.",
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T1 - Synthesis, biological evaluation, docking study and ulcerogenicity profiling of some novel quinoline-2-carboxamides as dual COXs/LOX inhibitors endowed with anti-inflammatory activity

AU - Abdelrahman, Mostafa H.

AU - Youssif, Bahaa G M

AU - abdelgawad, Mohamed A.

AU - Abdelazeem, Ahmed H.

AU - Ibrahim, Hussein M.

AU - Moustafa, Abd El Ghany A

AU - Treamblu, Laurent

AU - Syed Nasir Abbas, Bukhari

PY - 2017/2/15

Y1 - 2017/2/15

N2 - A series of novel quinoline-2-carboxamides 15–28 was synthesized and evaluated in vitro as dual COXs/LOX inhibitors. Compounds 19 and 27 exhibited the highest potency and selectivity for COX-2 inhibitory activity (IC50 = 1.21 and 1.13 μM, respectively; selectivity index (COX-1/COX-2) = 6.52 and 7.61, respectively) in comparison to the reference drug celecoxib (COX-2 IC50 = 0.88 μM; selectivity index (COX-1/COX-2) = 8.31). The anti-inflammatory activity of the newly synthesized compounds was further assessed in vivo using carrageenan induced paw edema assay. Interestingly, the in vitro results of COXs inhibitory assay were consistent with that of the in vivo assay where compounds 19 and 27 showed the highest anti-inflammatory activity with edema inhibition percentages of 59.38% and 65.03%, respectively compared to celecoxib (71.21%) after 5 h. Moreover, it was found that compounds 19 and 27 have a superior gastric safety profile comparable to indomethacin. The molecular docking study of compounds 19 and 27 into COX-2 active site suggested that these hits assumed binding pattern and interactions similar to that of bromocelecoxib (S-58) as a cocrystallized ligand explaining their remarkable COX-2 inhibitory activity and selectivity. Taken together, these results indicated that these derivatives are good leads for subsequent development into potential anti-inflammatory agents with least gastric damage.

AB - A series of novel quinoline-2-carboxamides 15–28 was synthesized and evaluated in vitro as dual COXs/LOX inhibitors. Compounds 19 and 27 exhibited the highest potency and selectivity for COX-2 inhibitory activity (IC50 = 1.21 and 1.13 μM, respectively; selectivity index (COX-1/COX-2) = 6.52 and 7.61, respectively) in comparison to the reference drug celecoxib (COX-2 IC50 = 0.88 μM; selectivity index (COX-1/COX-2) = 8.31). The anti-inflammatory activity of the newly synthesized compounds was further assessed in vivo using carrageenan induced paw edema assay. Interestingly, the in vitro results of COXs inhibitory assay were consistent with that of the in vivo assay where compounds 19 and 27 showed the highest anti-inflammatory activity with edema inhibition percentages of 59.38% and 65.03%, respectively compared to celecoxib (71.21%) after 5 h. Moreover, it was found that compounds 19 and 27 have a superior gastric safety profile comparable to indomethacin. The molecular docking study of compounds 19 and 27 into COX-2 active site suggested that these hits assumed binding pattern and interactions similar to that of bromocelecoxib (S-58) as a cocrystallized ligand explaining their remarkable COX-2 inhibitory activity and selectivity. Taken together, these results indicated that these derivatives are good leads for subsequent development into potential anti-inflammatory agents with least gastric damage.

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KW - Docking

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