新型吲哚美辛类似物作为选择性 COX-2 抑制剂：合成、COX-1/2 抑制活性、抗炎、致溃疡性、组织病理学和对接研究,Archiv der Pharmazie

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新型吲哚美辛类似物作为选择性 COX-2 抑制剂：合成、COX-1/2 抑制活性、抗炎、致溃疡性、组织病理学和对接研究
Archiv der Pharmazie ( IF 4.3 ) Pub Date : 2020-12-13 , DOI: 10.1002/ardp.202000328
Khaled R A Abdellatif _{1,

2} , Eman K A Abdelall ₁ , Heba A H Elshemy ₁ , El-Shaymaa El-Nahass ₃ , Maha M Abdel-Fattah ₄ , Yasmin Y M Abdelgawad ₁

Affiliation

合成了新的吲哚美辛类似物 4a-g、5、6、8a 和 8b，以克服吲哚美辛的非选择性和溃疡倾向。与塞来昔布 (IC50 = 0.89 μМ) 相比，所有新合成的化合物对环加氧酶 2 (COX-2；IC50 值范围：0.09-0.4 μМ) 的作用更强。与吲哚美辛 (SI = 1.14) 和塞来昔布 (SI = 3.52) 相比，化合物 4a、4b、4d、5 和 6 显示出最高的 COX-2 选择性指数（SI 范围 = 4.07-6.33）。此外，5 小时后，相对于塞来昔布 (78.96%) 和吲哚美辛 (90.43%)，4a、4b、4d、5 和 7 显示出良好的抗炎活性和水肿抑制 (79.36-88.8%)。此外，还评估了最有效的类似物 4b、4d、5 和 6 的致溃疡作用和组织病理学检查，以确定它们的安全性。结果可以阐明吲哚美辛类似物 5 作为一种显着的抗炎先导化合物，具有良好的安全性（溃疡指数 = 10.62），接近于非致溃疡药物塞来昔布（溃疡指数 = 10.53）并且优于吲哚美辛（溃疡指数 = 18.50） . 在 COX-2 活性位点对最活跃的化合物进行了对接研究，以测试其选择性并确认其作用机制。

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New indomethacin analogs as selective COX‐2 inhibitors: Synthesis, COX‐1/2 inhibitory activity, anti‐inflammatory, ulcerogenicity, histopathological, and docking studies

New indomethacin analogs 4a-g, 5, 6, 8a, and 8b were synthesized to overcome the nonselectivity and ulcer liability of indomethacin. All newly synthesized compounds were more potent against cyclooxygenase 2 (COX-2; IC50 value range: 0.09-0.4 μМ) as compared with celecoxib (IC50 = 0.89 μМ). Compounds 4a, 4b, 4d, 5, and 6 showed the highest COX-2 selectivity index (SI range = 4.07-6.33) as compared with indomethacin (SI = 1.14) and celecoxib (SI = 3.52). Additionally, 4a, 4b, 4d, 5, and 7 showed good anti-inflammatory activity with edema inhibition (79.36-88.8%), relative to celecoxib (78.96%) and indomethacin (90.43%), after 5 h. Also, ulcerogenic effects and histopathological examination were assessed for the most potent analogs, 4b, 4d, 5, and 6, to determine their safety. The results can shed light on indomethacin analog 5 as a remarkable anti-inflammatory lead compound with a good safety profile (ulcer index = 10.62) close to the nonulcerogenic drug celecoxib (ulcer index = 10.53) and better than indomethacin (ulcer index = 18.50). Docking studies were performed in the COX-2 active site for the most active compounds, to test their selectivity and to confirm their mechanism of action.

更新日期：2020-12-13

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