title: Flurbiprofen-antioxidant mutual prodrugs as safer nonsteroidal anti-inflammatory drugs: synthesis, pharmacological investigation, and computational molecular modeling.
abstract: 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.
authors.affiliation: Department of Chemistry, Allama Iqbal Open University, Islamabad, Pakistan; Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, Republic of Korea.
authors.forename: Zaman
authors.initials: Z
authors.lastname: Ashraf
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Sargodha, Sargodha, Pakistan.
authors.lastname: Alamgeer
authors.affiliation: Department of Chemistry, Allama Iqbal Open University, Islamabad, Pakistan.
authors.forename: Munazza
authors.initials: M
authors.lastname: Kanwal
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, Republic of Korea.
authors.forename: Mubashir
authors.initials: M
authors.lastname: Hassan
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Sargodha, Sargodha, Pakistan.
authors.forename: Sahar
authors.initials: S
authors.lastname: Abdullah
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Sargodha, Sargodha, Pakistan.
authors.forename: Mamuna
authors.initials: M
authors.lastname: Waheed
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Sargodha, Sargodha, Pakistan.
authors.forename: Haseeb
authors.initials: H
authors.lastname: Ahsan
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, Republic of Korea.
authors.forename: Song Ja
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000284:Administration, Oral; D000418:Albumins; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002351:Carrageenan; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D005480:Flurbiprofen / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000418:Albumins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D011355:Prodrugs; D005480:Flurbiprofen; D002351:Carrageenan
keywords: NSAIDs; flurbiprofen prodrugs; molecular docking; molecular dynamic simulation; natural antioxidants; pharmacological investigation