Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; Department of Pharmaceutical Sciences, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Bioorg Chem. 2020 Dec;105:104418. doi: 10.1016/j.bioorg.2020.104418. Epub 2020 Oct 22.
A novel series of halogenated triarylpyrazoles 12a-l was designed and synthesized. All target compounds showed good in vitro COX-2 inhibitory activity (IC = 0.043-0.17 µM) over COX-1 (IC = 7.8 - 15.4 µM) relative to celecoxib (COX-1/IC = 9.87, COX-2/IC = 0.055), with acceptable selectivity index values (SI = 50.6-253.1). Also, they displayed moderate to potent in vivo anti-inflammatory activity (% edema inhibition = 16.9-87.9) comparable to celecoxib (% edema inhibition = 46.6-72.1) as standard drug. Three fluorinated pyrazoles 12a, 12g and 12j, exhibited superior anti-inflammatory activity at all time intervals (% edema inhibition = 42.1-87.9) with better gastric profile (UI = 1.25-2.5) than the traditional NSAID; indomethacin (UI = 14) and were close to the selective COX-2 inhibitor; celecoxib (UI = 1.75). In-silico docking and ADME studies of 12a, 12g and 12j supported the obtained biological data and pointed out their potential use for the development of bio-available, safe and potent anti-inflammatory drugs.
设计并合成了一系列新型卤代三芳基吡唑 12a-l。所有目标化合物均表现出良好的体外 COX-2 抑制活性（IC = 0.043-0.17 µM），相对于塞来昔布（COX-1/IC = 9.87，COX-2/IC = 0.055），对 COX-1 的选择性较高，具有可接受的选择性指数值（SI = 50.6-253.1）。此外，它们还表现出中度至较强的体内抗炎活性（%水肿抑制率 = 16.9-87.9），与作为标准药物的塞来昔布（%水肿抑制率 = 46.6-72.1）相当。三个氟代吡唑 12a、12g 和 12j 在所有时间间隔内均表现出优异的抗炎活性（%水肿抑制率 = 42.1-87.9），且胃安全性（UI = 1.25-2.5）优于传统 NSAID；吲哚美辛（UI = 14），与选择性 COX-2 抑制剂塞来昔布（UI = 1.75）接近。12a、12g 和 12j 的计算机对接和 ADME 研究支持了获得的生物学数据，并指出它们有可能用于开发具有生物利用度、安全性和有效性的抗炎药物。
Acta Pharm Sin B. 2022-6
J Enzyme Inhib Med Chem. 2021-12
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