title: Design, synthesis of 2,3-disubstitued 4(3H)-quinazolinone derivatives as anti-inflammatory and analgesic agents: COX-1/2 inhibitory activities and molecular docking studies.
abstract: A new series, 2-substituted mercapto-3-[2-(pyridin-2-yl)ethyl]-4(3H)-quinazolinone 1-21, was synthesized and evaluated for in vivo anti-inflammatory and analgesic activities and in vitro COX-1/COX-2 inhibition. Compounds 1, 4, 5, 6, 8, 10, 13, 14, 15, 16, and 17 exhibited potent anti-inflammatory and analgesic properties, with ED50 values of 50.3-112.1mg/kg and 12.3-111.3mg/kg, respectively. These values may be compared with those of diclofenac sodium (ED50=112.2 and 100.4mg/kg) and celecoxib (ED50=84.3 and 71.6mg/kg). Compounds 4 and 6 possessed strong COX-2 inhibitory activity with IC50 (0.33μM and 0.40μM, respectively) and selectivity index (SI>303.0 and >250.0, respectively) values that are similar to those of the reference drug celecoxib (IC50 0.30μM and COX-2 SI>333). Compounds 5, 8, and 13 demonstrated effective COX-2 inhibitory activity with IC50 values of 0.70-0.80μM and COX-2 SI>125-142. Potent COX-2 inhibitors, such as compounds 4, 6, and 13, were docked into the active site pockets of COX-1 and COX-2, with the greatest recognition occurring at the COX-2 binding site and insignificant interactions at the binding site of the COX-1 pocket.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: alaa_moenes@yahoo.com.
authors.forename: Alaa A-M
authors.initials: AA
authors.lastname: Abdel-Aziz
authors.affiliation: Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Laila A
authors.initials: LA
authors.lastname: Abou-Zeid
authors.affiliation: Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Kamal Eldin H
authors.initials: KE
authors.lastname: ElTahir
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, AlKharj, Saudi Arabia; Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
authors.forename: Menshawy A
authors.initials: MA
authors.lastname: Mohamed
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Abu El-Enin
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt. Electronic address: adelazaba@yahoo.com.
authors.forename: Adel S
authors.initials: AS
authors.lastname: El-Azab
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D020128:Inhibitory Concentration 50; D051379:Mice; D062105:Molecular Docking Simulation; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013057:Spectrum Analysis / Q000379:methods
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D052999:Quinazolinones
keywords: 4(3H)-Quinazolinone; Anti-inflammatory activity; COX-1/COX-2 inhibition assay; Docking study; Synthesis