Flurbiprofen-antioxidant mutual prodrugs as safer nonsteroidal anti-inflammatory drugs: synthesis, pharmacological investigation, and computational molecular modeling

被引:21
作者
Ashraf, Zaman [1 ,2 ]
Alamgeer [3 ]
Kanwal, Munazza [1 ]
Hassan, Mubashir [2 ]
Abdullah, Sahar [3 ]
Waheed, Mamuna [3 ]
Ahsan, Haseeb [3 ]
Kim, Song Ja [2 ]
机构
[1] Allama Iqbal Open Univ, Dept Chem, Islamabad, Pakistan
[2] Kongju Natl Univ, Dept Biol Sci, Coll Nat Sci, Gongju, South Korea
[3] Univ Sargodha, Dept Pharmacol, Fac Pharm, Sargodha, Pakistan
来源
DRUG DESIGN DEVELOPMENT AND THERAPY | 2016年 / 10卷
关键词
flurbiprofen prodrugs; natural antioxidants; molecular docking; molecular dynamic simulation; pharmacological investigation; NSAIDs; POTENTIAL PRODRUGS; HIGH-THROUGHPUT; PROTEIN; ACID; IBUPROFEN; PLATFORM; EXTRACT; DOCKING; ASPIRIN; ESTERS;
D O I
10.2147/DDDT.S109318
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Flurbiprofen-antioxidant mutual prodrugs were synthesized to reduce the gastrointestinal (GI) effects associated with flurbiprofen. For reducing the GI toxicity, the free carboxylic group (-COOH) was temporarily masked by esterification with phenolic -OH of natural antioxidants vanillin, thymol, umbelliferone, and sesamol. The in vitro hydrolysis of synthesized prodrugs showed that they were stable in buffer solution at pH 1.2, indicating their stability in the stomach. The synthesized prodrugs undergo significant hydrolysis in 80% human plasma and thus release free flurbiprofen. The minimum reversion was observed at pH 1.2, suggesting that prodrugs are less irritating to the stomach than flurbiprofen. The anti-inflammatory, analgesic, antipyretic, and ulcerogenic activities of prodrugs were evaluated. All the synthesized prodrugs significantly (P<0.001) reduced the inflammation against carrageenan and egg albumin-induced paw edema at 4 hours of study. The reduction in the size of the inflamed paw showed that most of the compounds inhibited the later phase of inflammation. The prodrug 2-oxo-2H-chromen-7-yl-2-(2-fluorobiphenyl-4-yl)propanoate (4b) showed significant reduction in paw licking with percentage inhibition of 58%. It also exhibited higher analgesic activity, reducing the number of writhes with a percentage of 75%, whereas flurbiprofen showed 69% inhibition. Antipyretic activity was investigated using brewer's yeast-induced pyrexia model, and significant (P<0.001) reduction in rectal temperature was shown by all prodrugs at all times of assessment. The results of ulcerogenic activity showed that all prodrugs produced less GI irritation than flurbiprofen. Molecular docking and simulation studies were carried out with cyclooxygenase (COX-1 and COX-2) proteins, and it was observed that our prodrugs have more potential to selectively bind to COX-2 than to COX-1. It is concluded that the synthesized prodrugs have promising pharmacological activities with reduced GI adverse effects than the parent drug.
引用
收藏
页码:2401 / 2419
页数:19
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