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Design, Synthesis, Molecular Modelling, and Biological Evaluation of Oleanolic Acid-Arylidene Derivatives as Potential Anti-Inflammatory Agents
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2021-02-04 , DOI: 10.2147/dddt.s291784 Reyaz Hassan Mir 1 , Goutami Godavari 2 , Nasir Ali Siddiqui 3 , Bilal Ahmad 4 , Ramzi A Mothana 3 , Riaz Ullah 3 , Omer M Almarfadi 3 , Sanjay M Jachak 2 , Mubashir Hussain Masoodi 1
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2021-02-04 , DOI: 10.2147/dddt.s291784 Reyaz Hassan Mir 1 , Goutami Godavari 2 , Nasir Ali Siddiqui 3 , Bilal Ahmad 4 , Ramzi A Mothana 3 , Riaz Ullah 3 , Omer M Almarfadi 3 , Sanjay M Jachak 2 , Mubashir Hussain Masoodi 1
Affiliation
Introduction: Oleanolic acid, a pentacyclic triterpenic acid, is widely distributed in medicinal plants and is the most commonly studied triterpene for various biological activities, including anti-allergic, anti-cancer, and anti-inflammatory.
Methods: The present study was carried out to synthesize arylidene derivatives of oleanolic acid at the C-2 position by Claisen Schmidt condensation to develop more effective anti-inflammatory agents. The derivatives were screened for anti-inflammatory activity by scrutinizing NO production inhibition in RAW 264.7 cells induced by LPS and their cytotoxicity. The potential candidates were further screened for inhibition of LPS-induced interleukin (IL-6) and tumour necrosis factor-alpha (TNF-α) production in RAW 264.7 cells.
Results: The results of in vitro studies revealed that derivatives 3d, 3e, 3L, and 3o are comparable to that of the oleanolic acid on the inhibition of TNF-α and IL-6 release. However, derivative 3L was identified as the most potent inhibitor of IL-6 (77.2%) and TNF-α (75.4%) when compared to parent compound, and compounds 3a (77.18%), 3d (71.5%), and 3e (68.8%) showed potent inhibition of NO than oleanolic acid (65.22%) at 10μM. Besides, from docking score and Cyscore analysis analogs (3e, 3L, 3n) showed greater affinity towards TNF-α and IL-1β than dexamethasone.
Conclusion: Herein, we report a series of 15 new arylidene derivatives of oleanolic acid by Claisen Schmidt condensation reaction. All the compounds synthesized were screened for their anti-inflammatory activity against NO, TNF-α and IL-6. From the data, it was evident that most of the compounds exhibited better anti-inflammatory activity.
Keywords: LPS, natural products, IL-1β, IL-6, inflammation, RAW 264.7 cells
中文翻译：
齐墩果酸-亚芳基衍生物作为潜在抗炎剂的设计、合成、分子建模和生物学评价
简介：齐墩果酸是一种五环三萜酸，广泛分布于药用植物中，是最常被研究的具有多种生物活性的三萜，包括抗过敏、抗癌和抗炎。
方法：本研究通过Claisen Schmidt缩合合成齐墩果酸C-2位亚芳基衍生物，开发更有效的抗炎药。通过检查 LPS 诱导的 RAW 264.7 细胞中的 NO 产生抑制及其细胞毒性来筛选衍生物的抗炎活性。进一步筛选了潜在的候选者，以抑制 LPS 诱导的白细胞介素 (IL-6) 和 RAW 264.7 细胞中肿瘤坏死因子-α (TNF-α) 的产生。
结果：体外研究结果表明，衍生物3d、3e、3L和3o对TNF-α和IL-6释放的抑制作用与齐墩果酸相当。然而，与母体化合物、化合物 3a (77.18%)、3d (71.5%) 和 3e 相比，衍生物 3L 被确定为最有效的 IL-6 (77.2%) 和 TNF-α (75.4%) 抑制剂。 68.8%) 在 10μM 时对 NO 的抑制作用比齐墩果酸 (65.22%) 强。此外，从对接评分和 Cyscore 分析类似物（3e、3L、3n）显示出对 TNF-α 和 IL-1β 的亲和力高于地塞米松。
结论：在此，我们通过 Claisen Schmidt 缩合反应报告了一系列 15 种齐墩果酸的新亚芳基衍生物。筛选了所有合成的化合物对 NO、TNF-α 和 IL-6 的抗炎活性。从数据中可以看出，大多数化合物表现出更好的抗炎活性。
关键词： LPS，天然产物，IL-1β，IL-6，炎症，RAW 264.7 细胞
更新日期：2021-02-04
Methods: The present study was carried out to synthesize arylidene derivatives of oleanolic acid at the C-2 position by Claisen Schmidt condensation to develop more effective anti-inflammatory agents. The derivatives were screened for anti-inflammatory activity by scrutinizing NO production inhibition in RAW 264.7 cells induced by LPS and their cytotoxicity. The potential candidates were further screened for inhibition of LPS-induced interleukin (IL-6) and tumour necrosis factor-alpha (TNF-α) production in RAW 264.7 cells.
Results: The results of in vitro studies revealed that derivatives 3d, 3e, 3L, and 3o are comparable to that of the oleanolic acid on the inhibition of TNF-α and IL-6 release. However, derivative 3L was identified as the most potent inhibitor of IL-6 (77.2%) and TNF-α (75.4%) when compared to parent compound, and compounds 3a (77.18%), 3d (71.5%), and 3e (68.8%) showed potent inhibition of NO than oleanolic acid (65.22%) at 10μM. Besides, from docking score and Cyscore analysis analogs (3e, 3L, 3n) showed greater affinity towards TNF-α and IL-1β than dexamethasone.
Conclusion: Herein, we report a series of 15 new arylidene derivatives of oleanolic acid by Claisen Schmidt condensation reaction. All the compounds synthesized were screened for their anti-inflammatory activity against NO, TNF-α and IL-6. From the data, it was evident that most of the compounds exhibited better anti-inflammatory activity.
Keywords: LPS, natural products, IL-1β, IL-6, inflammation, RAW 264.7 cells
中文翻译：
齐墩果酸-亚芳基衍生物作为潜在抗炎剂的设计、合成、分子建模和生物学评价
简介：齐墩果酸是一种五环三萜酸，广泛分布于药用植物中，是最常被研究的具有多种生物活性的三萜，包括抗过敏、抗癌和抗炎。
方法：本研究通过Claisen Schmidt缩合合成齐墩果酸C-2位亚芳基衍生物，开发更有效的抗炎药。通过检查 LPS 诱导的 RAW 264.7 细胞中的 NO 产生抑制及其细胞毒性来筛选衍生物的抗炎活性。进一步筛选了潜在的候选者，以抑制 LPS 诱导的白细胞介素 (IL-6) 和 RAW 264.7 细胞中肿瘤坏死因子-α (TNF-α) 的产生。
结果：体外研究结果表明，衍生物3d、3e、3L和3o对TNF-α和IL-6释放的抑制作用与齐墩果酸相当。然而，与母体化合物、化合物 3a (77.18%)、3d (71.5%) 和 3e 相比，衍生物 3L 被确定为最有效的 IL-6 (77.2%) 和 TNF-α (75.4%) 抑制剂。 68.8%) 在 10μM 时对 NO 的抑制作用比齐墩果酸 (65.22%) 强。此外，从对接评分和 Cyscore 分析类似物（3e、3L、3n）显示出对 TNF-α 和 IL-1β 的亲和力高于地塞米松。
结论：在此，我们通过 Claisen Schmidt 缩合反应报告了一系列 15 种齐墩果酸的新亚芳基衍生物。筛选了所有合成的化合物对 NO、TNF-α 和 IL-6 的抗炎活性。从数据中可以看出，大多数化合物表现出更好的抗炎活性。
关键词： LPS，天然产物，IL-1β，IL-6，炎症，RAW 264.7 细胞
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