title: Synthesis, biological evaluation, docking study and ulcerogenicity profiling of some novel quinoline-2-carboxamides as dual COXs/LOX inhibitors endowed with anti-inflammatory activity.
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.
authors.affiliation: Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt.
authors.forename: Mostafa H
authors.initials: MH
authors.lastname: Abdelrahman
authors.affiliation: Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Aljouf, Sakaka2014, Saudi Arabia. Electronic address: bgyoussif@ju.edu.sa.
authors.forename: Bahaa G M
authors.initials: BGM
authors.lastname: Youssif
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Aljouf, Sakaka2014, Saudi Arabia; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Abdelgawad
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif 21974, Saudi Arabia.
authors.forename: Ahmed H
authors.initials: AH
authors.lastname: Abdelazeem
authors.affiliation: Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Aljouf University, Aljouf, Sakaka2014, Saudi Arabia.
authors.forename: Hussein M
authors.initials: HM
authors.lastname: Ibrahim
authors.affiliation: Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Aljouf University, Aljouf, Sakaka2014, Saudi Arabia; Histology Department, Faculty of Medicine, Al-Azhar University, Damietta, Egypt.
authors.forename: Abd El Ghany A
authors.initials: AEGA
authors.lastname: Moustafa
authors.affiliation: School of Natural and Computing Sciences, University of Aberdeen, Meston Building, Aberdeen, AB243UE, Ireland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Treamblu
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Aljouf, Sakaka2014, Saudi Arabia. Electronic address: snab_hussaini@yahoo.com.
authors.forename: Syed Nasir Abbas
authors.initials: SNA
authors.lastname: Bukhari
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D020134:Catalytic Domain; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D016859:Lipoxygenase Inhibitors / Q000009:adverse effects / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D062105:Molecular Docking Simulation; D011804:Quinolines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000473:pathology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2
keywords: Anti-inflammatory; COXs; Docking; LOX; Quinoline-2-carboxamides