Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt.
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Eur J Med Chem. 2014 Jun 10;80:416-22. doi: 10.1016/j.ejmech.2014.04.065. Epub 2014 Apr 24.
The reaction of arylsulfones 11a-d with hydrazonoyl chloride derivative 13 furnished celecoxib analogs 4-(3-acetyl-5-aryl-4-(arylsulfonyl)-1H-pyrazol-1-yl)benzenesulfonamides 15a-d, respectively. Oximes 16a, b and hydrazones 17a, b were prepared by reacting sulfones 11a, b with hydroxyl amine and phenyl hydrazine, respectively. The anti-inflammatory activity of the synthesized compounds showed that, 5-(4-bromophenyl)-4-(phenylsulfonyl)pyrazole 15c and 5-(4-bromophenyl)-4-(4-tolylsulfonyl)pyrazole 15d exhibited excellent anti-inflammatory activity with ED50 = 68 ± 2.2 and 51 ± 0.7 μM/kg, respectively, higher than that of celecoxib (ED50 = 86 ± 1.1 μM/kg) after 3 h with acceptable ulcer index. In addition, the LD50 of 15c and 15d is 7.1 mM/kg for each, and 9.8 mM/kg for celecoxib. Compound 15d appeared selectivity index (COX-2/COX-1) almost the half of celecoxib while 15c is non-selective for COX-2. Compound 15c with ED50 = 80 ± 2.8 μM/kg showed a significant analgesic activity when compared with celecoxib (ED50 = 70 ± 3.9 μM/kg) after 2 h whereas 15b (ED50 = 50 ± 1.2 μM/kg) and 15d (ED50 = 69 ± 2.7 μM/kg) seemed to be more potent than celecoxib (ED50 = 156 ± 4.8 μM/kg) but with a shorter duration (0.5 h).
芳基砜 11a-d 与酰肼氯衍生物 13 反应，分别得到塞来昔布类似物 4-(3-乙酰基-5-芳基-4-(芳基砜基)-1H-吡唑-1-基)苯磺酰胺 15a-d。砜 11a、b 分别与羟胺和苯肼反应得到肟 16a、b 和腙 17a、b。合成化合物的抗炎活性表明，5-(4-溴苯基)-4-(苯基砜基)吡唑 15c 和 5-(4-溴苯基)-4-(4-甲苯基砜基)吡唑 15d 表现出优异的抗炎活性，ED50 分别为 68 ± 2.2 和 51 ± 0.7 μM/kg，高于塞来昔布（ED50 = 86 ± 1.1 μM/kg），且溃疡指数可接受。此外，15c 和 15d 的 LD50 分别为 7.1 mM/kg 和 9.8 mM/kg，而塞来昔布为 9.8 mM/kg。化合物 15d 的选择性指数（COX-2/COX-1）几乎是塞来昔布的一半，而 15c 对 COX-2 是非选择性的。与塞来昔布（ED50 = 70 ± 3.9 μM/kg）相比，15c 在 2 小时时 ED50 为 80 ± 2.8 μM/kg，显示出显著的镇痛活性，而 15b（ED50 = 50 ± 1.2 μM/kg）和 15d（ED50 = 69 ± 2.7 μM/kg）似乎比塞来昔布（ED50 = 156 ± 4.8 μM/kg）更有效，但持续时间更短（0.5 小时）。
