Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen-Antioxidant Mutual Prodrugs.

Dexibuprofen-antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen - were obtained by reacting its -COOH group with chloroacetyl derivatives -. The in vitro hydrolysis data confirmed that synthesized prodrugs - 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 ( < 0.001) is more significant than the parent dexibuprofen. The prodrug produced maximum inhibition (42.06%) of paw-edema against egg-albumin induced inflammation in mice. Anti-pyretic effects in mice indicated that prodrugs and showed significant inhibition of pyrexia ( < 0.001). The analgesic activity of is more pronounced compared to other synthesized prodrugs. The mean percent inhibition indicated that the prodrug 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 - 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.