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<p>A novel series of antioxidant-conjugated mutual prodrugs of ibuprofen (RJ-02-01 to RJ-02-10) was designed and synthesized to address the gastrointestinal (GI) toxicity. Ibuprofen was covalently linked to substituted aniline-based antioxidant moieties through an amide bond. In-vitro hydrolysis results demonstrated the immense stability of the synthesized ibuprofen prodrugs in simulated gastric fluid (pH 1.2) with minimal drug release, indicating reduced potential for gastric irritation. Whereas enhanced hydrolysis was observed in simulated intestinal fluid (pH 7.4). Molecular docking revealed strong binding affinities for selected derivatives, with RJ-02-07 showing the most favorable interaction profile compared with ibuprofen. Biological evaluation identified RJ-02-07 as the lead compound, exhibiting significantly stronger COX-1 and COX-2 inhibitory activity than the parent drug. Cellular assays further demonstrated reduced reactive oxygen species levels, increased superoxide dismutase activity, and downregulation of COX-1/COX-2 protein expression, indicating improved antioxidant and anti-inflammatory potential. Cytotoxicity assessment showed lower toxicity relative to ibuprofen, suggesting a favorable safety profile. These findings suggest that this mutual prodrug strategy may reduce gastric exposure to free ibuprofen while enhancing the therapeutic efficacy; however, further in-vivo pharmacokinetic and gastro-protective studies will be required to confirm these potential benefits.</p>

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Design, synthesis, in-vitro hydrolysis and biological evaluation of antioxidant conjugated mutual prodrugs of ibuprofen

  • 期刊论文

  • 发表日期：

    2026年3月12日

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  • Rajat Goyal,
  • Prabodh Chander Sharma,
  • Sumeet Gupta

摘要

A novel series of antioxidant-conjugated mutual prodrugs of ibuprofen (RJ-02-01 to RJ-02-10) was designed and synthesized to address the gastrointestinal (GI) toxicity. Ibuprofen was covalently linked to substituted aniline-based antioxidant moieties through an amide bond. In-vitro hydrolysis results demonstrated the immense stability of the synthesized ibuprofen prodrugs in simulated gastric fluid (pH 1.2) with minimal drug release, indicating reduced potential for gastric irritation. Whereas enhanced hydrolysis was observed in simulated intestinal fluid (pH 7.4). Molecular docking revealed strong binding affinities for selected derivatives, with RJ-02-07 showing the most favorable interaction profile compared with ibuprofen. Biological evaluation identified RJ-02-07 as the lead compound, exhibiting significantly stronger COX-1 and COX-2 inhibitory activity than the parent drug. Cellular assays further demonstrated reduced reactive oxygen species levels, increased superoxide dismutase activity, and downregulation of COX-1/COX-2 protein expression, indicating improved antioxidant and anti-inflammatory potential. Cytotoxicity assessment showed lower toxicity relative to ibuprofen, suggesting a favorable safety profile. These findings suggest that this mutual prodrug strategy may reduce gastric exposure to free ibuprofen while enhancing the therapeutic efficacy; however, further in-vivo pharmacokinetic and gastro-protective studies will be required to confirm these potential benefits.