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

作者：Abdel Aziz Alaa A M^*; Abou Zeid Laila A; ElTahir Kamal Eldin H; Mohamed Menshawy A; Abu El Enin Mohamed A; El Azab Adel S^*

来源：Bioorganic & Medicinal Chemistry, 2016, 24(16): 3818-3828.

DOI：10.1016/j.bmc.2016.06.026

• Synthesis
• 4(3H)-Quinazolinone
• Anti-inflammatory activity
• COX-1/COX-2 inhibition assay
• Docking study

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 50.3-112.1 mg/kg and 12.3-111.3 mg/kg, respectively. These values may be compared with those of diclofenac sodium (ED50 = 112.2 and 100.4 mg/kg) and celecoxib (ED50 = 84.3 and 71.6 mg/kg). Compounds 4 and 6 possessed strong COX-2 inhibitory activity with IC50 (0.33 mu M and 0.40 mu M, respectively) and selectivity index (SI > 303.0 and > 250.0, respectively) values that are similar to those of the reference drug celecoxib (IC50 0.30 mu M and COX-2 SI > 333). Compounds 5, 8, and 13 demonstrated effective COX-2 inhibitory activity with IC50 values of 0.70-0.80 mu M 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.

• 出版日期2016-8-15