Synthesis and evaluation of mutual prodrugs of ibuprofen with menthol, thymol and eugenol

The present works deals with simple and efficient method of improving therapeutic efficacy of racemic ibuprofen by retarding gastrointestinal side effects through masking of carboxylic group chemically. This is achieved by synthesis and evaluation of ester derivatives of ibuprofen as mutual prodrugs with naturally occurring phenolic and alcoholic compounds. Promoieties like menthol; thymol and eugenol were selected with the aim of getting synergistic effect as these are natural analgesic having traditional medicinal values. Prodrugs are found to be highly lipophilic as compared to parent drug. All the prodrugs are found to be highly stable at acidic pH while undergoes hydrolysis at neutral and alkaline pH as indicated by their t1/2 values. Synthesized prodrugs derivatives show increased anti-inflammatory activity that might be attributed to synergistic effect as ibuprofen conjugates to natural analgesics. Ulcer index shows much reduction in gastric ulceration compared to ibuprofen concluding the successful masking of acidic group.

Graphical abstractAn enantiomeric mixture of targeted mutual prodrugs are achieved by reacting acidic group of racemic ibuprofen with hydroxy group of phenolic/alcoholic compounds like menthol, eugenol and thymol to afford the desired esters with the aid of N,N′ dicyclohexylcarbodiimide in presence of dichloromethane.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Mutual ester prodrugs of racemic ibuprofen were synthesized successfully. ► Prodrugs are more lipophilic than parent drug ibuprofen. ► Prodrugs show good stability at gastric pH. ► Minimize gastrointestinal toxicity and retention of activity improves effectiveness.