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<p>The enzymes cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) metabolize arachidonic acid and have been associated with the onset and progression of several disorders, including various inflammatory diseases. Dual COX-2/15-LOX inhibition is a useful approach to develop drugs with enhanced biological activities and reduced off-target drug actions, with a wider range of anti-inflammatory properties as compared to traditional NSAIDs. In the current work, we designed and developed a number of arylated carboxylate acetaminophen analogues as COX-2/15-LOX dual inhibitors. Compounds <b>5b</b>, <b>5d</b>, and <b>5e</b> exhibited moderate COX-2 inhibitory activity (IC<sub>50</sub> = 1.44 ± 0.10, 1.80 ± 0.14, &amp; 2.39 ± 0.11 µM) in vitro assay. Compound <b>5c</b> had higher COX-2 selectivity (IC<sub>50</sub> = 0.18 ± 0.05 µM) than celecoxib (IC<sub>50</sub> = 0.33 ± 011 µM). Compared to the quercetin (standard inhibitor), with an IC<sub>50</sub> = 15.8 ± 0.61 µM that all synthesized analogues exhibited significantly improved inhibitory activity towards 15-LOX and compound <b>5c</b> was found to be the most effective 15-LOX inhibitor (IC<sub>50</sub> = 0.14 ± 0.18 µM). Moreover, molecular docking closely aligns with in vitro studies, revealing the specific interactions towards synthesized derivatives (<b>5a</b>–<b>5f</b>) and target proteins.</p><p></p>

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Synthesis, hydrolysis, and COX-2/15-LOX inhibitory evaluation of 4-Acetamidophenyl 4-Bromobenzoates

  • 期刊论文

  • 发表日期：

    2025年3月17日

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  • Uzma Afzal,
  • Abid Mahmood,
  • Muhammad Zubair,
  • Nasir Rasool,
  • Aqsa Kanwal,
  • Maria Sohail,
  • Gulraiz Ahmad

摘要

The enzymes cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) metabolize arachidonic acid and have been associated with the onset and progression of several disorders, including various inflammatory diseases. Dual COX-2/15-LOX inhibition is a useful approach to develop drugs with enhanced biological activities and reduced off-target drug actions, with a wider range of anti-inflammatory properties as compared to traditional NSAIDs. In the current work, we designed and developed a number of arylated carboxylate acetaminophen analogues as COX-2/15-LOX dual inhibitors. Compounds 5b, 5d, and 5e exhibited moderate COX-2 inhibitory activity (IC50 = 1.44 ± 0.10, 1.80 ± 0.14, & 2.39 ± 0.11 µM) in vitro assay. Compound 5c had higher COX-2 selectivity (IC50 = 0.18 ± 0.05 µM) than celecoxib (IC50 = 0.33 ± 011 µM). Compared to the quercetin (standard inhibitor), with an IC50 = 15.8 ± 0.61 µM that all synthesized analogues exhibited significantly improved inhibitory activity towards 15-LOX and compound 5c was found to be the most effective 15-LOX inhibitor (IC50 = 0.14 ± 0.18 µM). Moreover, molecular docking closely aligns with in vitro studies, revealing the specific interactions towards synthesized derivatives (5a–5f) and target proteins.