Bansal Yogita, Kaur Maninder, Silakari Om
Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India.
Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India.
Eur J Med Chem. 2015 Jan 7;89:671-82. doi: 10.1016/j.ejmech.2014.10.081. Epub 2014 Oct 30.
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.
布洛芬（IB）和美沙拉嗪（MES）是常用的非甾体抗炎药，而苯并咪唑（BZ）和2-氨基苯并咪唑（ABZ）是具有免疫调节活性的重要药效基团。在本研究中，将IB和MES与不同取代的BZ或ABZ核偶联，合成了IB-BZ（2a - 2e）、IB-ABZ（3a - 3e）、MES-BZ（4a - 4e）和MES-ABZ（5a - 5e）嵌合共轭物，作为可引发抗炎和免疫调节活性的新型化合物。每种化合物都保留了母体非甾体抗炎药的抗炎活性。发现BZ共轭物（2和4）具有免疫刺激作用，而ABZ共轭物（3和5）具有免疫抑制作用。每种化合物还表现出良好的抗氧化活性，这归因于富含电子的BZ和ABZ核。化合物2a、2e、3a、3e和5b表现出最显著的抗炎和免疫调节活性。因此，对它们进行了体内急性胃溃疡形成性评估。这些化合物对胃黏膜是安全的，这可能是由于IB和MES的游离-COOH基团被掩盖，和/或由于BZ核本身。BZ和ABZ 5位的苯甲酰基具有最大的免疫刺激活性。相比之下，-NO2基团具有最大的免疫抑制作用。对接分析表明这些化合物对COX-2酶更具选择性，这支持了它们的胃保护活性。这些结果表明，这些化合物可作为开发治疗免疫相关炎症性疾病（如癌症和类风湿性关节炎）新药的先导物。
