Benzimidazole–ibuprofen/mesalamine conjugates: Potential candidates for multifactorial diseases

• IB/MES–NSAID conjugates designed and synthesized.
• All compounds showed anti-inflammatory activity equivalent to the parent NSAID.
• All compounds also showed mild to good immunomodulatory activity.
• Docking analysis proved compounds more selective to COX-2 and less ulcerogenic.
• The compounds may be useful in treatment of multifactorial diseases.

Ibuprofen (IB) and mesalamine (MES) are commonly used NSAIDs whereas benzimidazole (BZ) and 2-aminobenzimidazole (ABZ) are important pharmacophore for immunomodulatory activities. In the present study, IB and MES were coupled with variedly substituted BZ or ABZ nucleus to synthesize IB–BZ (2a–2e), IB–ABZ (3a–3e), MES–BZ (4a–4e) and MES–ABZ (5a–5e) chimeric conjugates as novel compounds that could elicit both anti-inflammatory and immunomodulatory activities. Each compound retained the anti-inflammatory activity of the parent NSAID. The BZ conjugates (2 and 4) were found immunostimulatory whereas the ABZ conjugates (3 and 5) were immunosuppressive. Each compound also exhibited good antioxidant activity, which is attributed to the electron rich BZ and ABZ nuclei. Compound 2a, 2e, 3a, 3e and 5b exhibited the most significant anti-inflammatory and immunomodulatory activities. Hence, these were evaluated for in vivo acute gastric ulcerogenicity. The compounds were safe to gastric mucosa, probably due to masking of the free –COOH group of IB and MES, and/or to the BZ nucleus itself. A benzoyl group at 5-position of BZ and ABZ incurred maximum immunostimulatory activity. In contrast, a –NO2 group incurred the maximum immunosuppressive action. Docking analysis revealed the compounds to be more selective towards COX-2 enzyme, which support the gastroprotective activity. These results suggest that the compounds can be taken as lead for development of new drugs for the treatment of immune related inflammatory disorders, such as cancer and rheumatoid arthritis.

Conjugates of ibuprofen and mesalamine were designed and synthesized. These exhibited anti-inflammatory and immunostimulatory or immunosuppressive effects. The compounds were more selective towards COX-2 enzyme, and therefore less ulcerogenic.Figure optionsDownload as PowerPoint slide