Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen-Antioxidant Mutual Prodrugs.
Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen-Antioxidant Mutual Prodrugs.
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DOI：
10.3390/ijms17122151
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发表时间：
2016-12-21
影响因子：
5.6
通讯作者：
Kim SJ
中科院分区：
文献类型：
--
作者：
Ashraf Z;Alamgeer;Rasool R;Hassan M;Ahsan H;Afzal S;Afzal K;Cho H;Kim SJ
合成了右旋布洛芬-抗氧化剂缀合物，目的是降低其胃肠道效应。通过使其-COOH基团与氯乙酰基衍生物3a-c反应获得地塞米松5a-c的酯类似物。体外水解数据证实，合成的前药5a-c在胃中稳定，而在80%人血浆中经历显著水解，从而释放游离的地塞米松。在pH 1.2下观察到最小回复，表明前药对胃的刺激性低于地塞米松。5c的抗炎活性（p < 0.001）明显高于母体地塞米松。前药5c对卵清蛋白诱导的小鼠足肿胀有最大抑制作用（42.06%）。对小鼠的解热作用表明，前药5a和5 b显示出显著的抑制发热（p < 0.001）。与其他合成的前药相比，5a的镇痛活性更显著。平均抑制百分比表明，前药5a在减少乙酸诱导的扭体次数方面比标准地塞米松更有活性。致溃疡活性结果证实合成的前药产生的胃肠道不良反应比地塞米松少。体外抗血小板聚集活性结果也证实合成的前药对胃肠道粘膜的刺激性低于母体右旋糖酐。分子对接分析表明，前药5a-c与靶蛋白活性结合位点的残基相互作用。通过分子动力学模拟研究验证了药物-靶点复合物的稳定性。结果表明，合成的前药与考克斯-2蛋白形成稳定的复合物，从而支持我们的湿实验室结果。因此，可以得出结论，合成的前药具有良好的药理活性，胃肠道不良反应比母体药物减少。
Dexibuprofen–antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen 5a–c were obtained by reacting its –COOH group with chloroacetyl derivatives 3a–c. The in vitro hydrolysis data confirmed that synthesized prodrugs 5a–c were stable in stomach while undergo significant hydrolysis in 80% human plasma and thus release free dexibuprofen. The minimum reversion was observed at pH 1.2 suggesting that prodrugs are less irritating to stomach than dexibuprofen. The anti-inflammatory activity of 5c (p < 0.001) is more significant than the parent dexibuprofen. The prodrug 5c produced maximum inhibition (42.06%) of paw-edema against egg-albumin induced inflammation in mice. Anti-pyretic effects in mice indicated that prodrugs 5a and 5b showed significant inhibition of pyrexia (p < 0.001). The analgesic activity of 5a is more pronounced compared to other synthesized prodrugs. The mean percent inhibition indicated that the prodrug 5a was more active in decreasing the number of writhes induced by acetic acid than standard dexibuprofen. The ulcerogenic activity results assured that synthesized prodrugs produce less gastrointestinal adverse effects than dexibuprofen. The ex vivo antiplatelet aggregation activity results also confirmed that synthesized prodrugs are less irritant to gastrointestinal mucosa than the parent dexibuprofen. Molecular docking analysis showed that the prodrugs 5a–c interacts with the residues present in active binding sites of target protein. The stability of drug–target complexes is verified by molecular dynamic simulation study. It exhibited that synthesized prodrugs formed stable complexes with the COX-2 protein thus support our wet lab results. It is therefore concluded that the synthesized prodrugs have promising pharmacological activities with reduced gastrointestinal adverse effects than the parent drug.
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影响因子：
5.6
作者：
Elengoe A;Naser MA;Hamdan S
通讯作者：
Hamdan S
影响因子：
5.8
作者：
Kaehler, S. T.;Phleps, W.;Hesse, E.
通讯作者：
Hesse, E.
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
2.4
作者：
Amiri, Shiva;Sansom, Mark S. P.;Biggin, Philip C.
通讯作者：
Biggin, Philip C.
影响因子：
7.3
作者：
BENTLEY, GA;NEWTON, SH;STARR, J
通讯作者：
STARR, J