Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia.
School of Pharmacy, Aristotle, University of Thessaloniki, 54124 Thessaloniki, Greece.
Molecules. 2023 Apr 12;28(8):3416. doi: 10.3390/molecules28083416.
Major obstacles faced by the use of nonsteroidal anti-inflammatory drugs (NSAID) are their gastrointestinal toxicity induced by non-selective inhibition of both cyclooxygenases (COX) 1 and 2 and their cardiotoxicity associated with a certain class of COX-2 selective inhibitors. Recent studies have demonstrated that selective COX-1 and COX-2 inhibition generates compounds with no gastric damage. The aim of the current study is to develop novel anti-inflammatory agents with a better gastric profile. In our previous paper, we investigated the anti-inflammatory activity of 4-methylthiazole-based thiazolidinones. Thus, based on these observations, herein we report the evaluation of anti-inflammatory activity, drug action, ulcerogenicity and cytotoxicity of a series of 5-adamantylthiadiazole-based thiazolidinone derivatives. The in vivo anti-inflammatory activity revealed that the compounds possessed moderate to excellent anti-inflammatory activity. Four compounds , , and showed highest potency (62.0, 66.7, 55.8 and 60.0%, respectively), which was higher than the control drug indomethacin (47.0%). To determine their possible mode of action, the enzymatic assay was conducted against COX-1, COX-2 and LOX. The biological results demonstrated that these compounds are effective COX-1 inhibitors. Thus, the IC values of the three most active compounds , and as COX-1 inhibitors were 1.08, 1.12 and 9.62 μΜ, respectively, compared to ibuprofen (12.7 μΜ) and naproxen (40.10 μΜ) used as control drugs. Moreover, the ulcerogenic effect of the best compounds , and were evaluated and revealed that no gastric damage was observed. Furthermore, compounds were found to be nontoxic. A molecular modeling study provided molecular insight to rationalize the COX selectivity. In summary, we discovered a novel class of selective COX-1 inhibitors that could be effectively used as potential anti-inflammatory agents.
使用非甾体抗炎药（NSAID）面临的主要障碍是其通过非选择性抑制环加氧酶（COX）1 和 2 引起的胃肠道毒性，以及与某些 COX-2 选择性抑制剂相关的心脏毒性。最近的研究表明，选择性 COX-1 和 COX-2 抑制会产生无胃损伤的化合物。本研究旨在开发具有更好胃谱的新型抗炎药。在我们之前的论文中，我们研究了基于 4-甲基噻唑的噻唑烷酮的抗炎活性。因此，基于这些观察结果，本文报告了一系列基于 5-金刚烷基噻二唑的噻唑烷酮衍生物的抗炎活性、药物作用、致溃疡作用和细胞毒性的评估。体内抗炎活性表明，这些化合物具有中度至极好的抗炎活性。四种化合物 、 、 和 表现出最高的效力（分别为 62.0%、66.7%、55.8%和 60.0%），高于对照药物吲哚美辛（47.0%）。为了确定它们可能的作用模式，对 COX-1、COX-2 和 LOX 进行了酶测定。生物结果表明，这些化合物是有效的 COX-1 抑制剂。因此，三种最活跃的化合物 、 和 作为 COX-1 抑制剂的 IC 值分别为 1.08、1.12 和 9.62 μΜ，而作为对照药物的布洛芬（12.7 μΜ）和萘普生（40.10 μΜ）。此外，还评估了最佳化合物 、 和 的致溃疡作用，结果表明没有胃损伤。此外，发现化合物没有毒性。分子建模研究提供了分子见解，以合理化 COX 的选择性。总之，我们发现了一类新型的选择性 COX-1 抑制剂，可有效用作潜在的抗炎药。
