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Design, synthesis, analgesic, anti-inflammatory activity of novel pyrazolones possessing aminosulfonyl pharmacophore as inhibitors of COX-2/5-LOX enzymes: Histopathological and docking studies
Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2018-03-08 , DOI: 10.1016/j.bioorg.2018.03.011
Mohamed A. Abdelgawad , Madlen B. Labib , Waleed A.M. Ali , Gehan Kamel , Amany A. Azouz , EL-Shaymaa EL-Nahass

A series of newly synthesized 4-aryl-hydrazonopyrazolones were designed and their structures were confirmed by spectral and elemental analyses. All synthesized compounds were evaluated for their in vitro COXs, 5-LOX inhibition, in vivo analgesic and anti-inflammatory activities. Compounds 5d, 5f and 5i were found to be the most potent COX-2/5-LOX inhibitors with superior COX-2 selectivity index values (SI = 5.29–5.69) to reference standard celecoxib (SI = 3.52). Four compounds; 5b, 5c, 5d and 5f showed excellent anti-inflammatory activity (% edema inhibition = 72.72–54.54%) and perfect ED50 values (ED50 = 0.044–0.104 mmol/kg) relative to celecoxib (ED50 = 0.032 mmol/kg). To explore the most active compounds, ulcerogenic effect on stomach in comparison with indomethacin and celecoxib in addition to histopathological investigations were performed. Compound 5f showed better gastric profile (UI = 2.33) than celecoxib (UI = 3.00). Also, 5f caused 50% increase in thermal pain threshold close to reference drug indomethacin (53.13%). Docking study of all the target compounds into COX-2 and 5-LOX active sites was performed to rational their anti-inflammatory activities.



中文翻译:

具有氨基磺酰基药效团作为COX-2 / 5-LOX酶抑制剂的新型吡唑啉酮的设计,合成,镇痛,抗炎活性:组织病理学和对接研究

设计了一系列新合成的4-芳基-肼基并吡唑啉酮,并通过光谱和元素分析证实了它们的结构。评价所有合成的化合物的体外COX,5-LOX抑制,体内止痛和抗炎活性。发现化合物5d5f5i是最有效的COX-2 / 5-LOX抑制剂,其COX-2选择性指数值(SI = 5.29–5.69)优于参考标准塞来昔布(SI = 3.52)。四种化合物;5b5c5d5f表现出出色的抗炎活性(抑制水肿百分比= 72.72–54.54%)和ED 50完美 相对于塞来昔布(ED 50  = 0.032 mmol / kg)的数值(ED 50 = 0.044-0.104 mmol / kg)。为了研究最具活性的化合物,除了进行了组织病理学研究外,还与吲哚美辛和塞来昔布相比对胃有致溃疡作用。与塞来昔布(UI = 3.00)相比,化合物5f的胃部分布更好(UI = 2.33)。同样,5f导致热痛阈值增加50%,接近参考药物消炎痛(53.13%)。进行了将所有目标化合物对接至COX-2和5-LOX活性位点的研究,以合理化其抗炎活性。

更新日期:2018-03-08
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