Abstract
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.
Highlights
Ibuprofen, (R,S-2-(4-isobutylphenyl)-propionic acid) a non-steroidal anti-inflammatory drug exists in two enantiomeric forms which are present in the racemate [1]
For the first time natural antioxidants menthol, sesamol and umbelliferon were used for the preparation of mutual prodrugs of dexibuprofen
The synthesized prodrugs are stable in gastric mucosa at pH 1.2 and are not hydrolyzed to free dexibuprofen
Summary
Ibuprofen, (R,S-2-(4-isobutylphenyl)-propionic acid) a non-steroidal anti-inflammatory drug exists in two enantiomeric forms which are present in the racemate [1]. Dexibuprofen, S-(+)-ibuprofen is pharmacologically more active than racemic ibuprofen which has equal quantities of R-(−) and S-(+) enantiomers [2]. In the dose ratio of 1:0.5 (Racemic ibuprofen vs dexibuprofen), at least equivalent efficacy was proven in acute mild to severe somatic and visceral pain models. The physico-chemical properties of dexibuprofen are different than the racemic ibuprofen. Dexibuprofen has a slower dissolution rate in the simulated gastric and enteric juices compared with the racemic ibuprofen [3]. Dexibuprofen possesses comparable pharmacological efficacy and tolerability to that of diclofenac, naproxen and celecoxib [4]
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