一些4,5-二氢噻吩并[3,2-e][1,2,4]三唑并[4,3-a]嘧啶-2-甲酰胺作为抗炎和镇痛剂的合成

Synthesis of Some 4,5-Dihydrothieno[3,2-e][1,2,4]Triazolo[4,3-a] Pyrimi-dine-2-Carboxamides as Anti-Inflammatory and Analgesic Agents.

作者信息

Shaaban Omaima G, Rizk Ola H, Bayad Aida E, El-Ashmawy Ibrahim M

机构信息

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria 21521, Egypt;

Univ. Fellow, Veterinary Services Unit, Faculty of Veterinary Medicine, University of Alexandria, Egypt;

出版信息

Open Med Chem J. 2013 Nov 29;7:49-65. doi: 10.2174/1874104501307010039. eCollection 2013.

A new series 4,5-dihydrothieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidine-2-carboxamide was synthesized. Twenty one newly synthesized compounds were investigated for their anti-inflammatory and analgesic activity using acute and subacute formalin-induced paw edema models and diclofenac Na as a reference. The acute toxicity (ALD50) and ulcerogenic effects of the active compounds were also determined. The thienotriazolopyrimidines 10a, 10c and 11c were found to exhibit remarkable anti-inflammatory activity at both models in addition to good analgesic activity with a delayed onset of action. Moreover, the active compounds showed high GI safety level and are well tolerated by experimental animals with high safety margin (ALD50 > 0.4 g/kg). Docking study using Molecular Operating Environment (MOE) version 2008.10 into COX-2 has been made for derivatives of highest anti-inflammatory activity.

合成了一种新的4,5-二氢噻吩并[3,2-e][1,2,4]三唑并[4,3-a]嘧啶-2-甲酰胺系列。使用急性和亚急性福尔马林诱导的爪肿胀模型，并以双氯芬酸钠作为参考，对21种新合成的化合物进行了抗炎和镇痛活性研究。还测定了活性化合物的急性毒性（ALD50）和致溃疡作用。发现噻吩并三唑并嘧啶10a、10c和11c在两种模型中均表现出显著的抗炎活性，此外还具有良好的镇痛活性，且作用起效延迟。此外，活性化合物显示出较高的胃肠道安全水平，实验动物对其耐受性良好，安全 margin 较高（ALD50 > 0.4 g/kg）。已使用2008.10版分子操作环境（MOE）对具有最高抗炎活性的衍生物进行了COX-2对接研究。