In diseases like atherosclerosis, rheumatoid arthritis, and sepsis, phospholipase A2 (PLA2) and proteinase K play a role in inflammation by releasing arachidonic acid (AA). The crucial step in the inflammatory process is believed to be the release of prostaglandins after PLA2 mobilizes AA. Drugs obstructing the COX and LOX pathways in the arachidonic acid cascade, drugs that inhibit these enzymes can treat inflammatory processes. To combat against these inflammatory promoters,the authors herein report an effective method for the synthesis of a series of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives (4a–h) under the effect of TiO as a photocatalyst in ethanolic medium, and their effect against phospholipase A2, as well as proteinase K, was evaluated. The results confirmed that using TiO (20 mg) as a photocatalyst exhibits excellent performance in terms of yield and reaction time. The yield of all the synthesized compounds is between 79 and 91 % in just 60 min. After closely evaluating the SAR of the examined compounds against both enzymes, it was discovered that compounds (4b, 4f) with electron-donating substituents have higher PLA2 inhibitory (%) activity than those with electron-removing substituents (4a, 4e). Compounds (4c, 4d) containing heterocyclic rings showed significantly higher proteinase inhibitory (%) activity when compared to other electron-donating or withdrawing compounds. It was further confirmed that studied compounds against both enzymes exhibited dose-dependent behavior. We studied the intermolecular interactions of the compounds by molecular docking with human non-pancreatic secretory phospholipase A2 and proteinase K. We evaluated the dynamical stability of the docked complexes using a 100 ns molecular dynamics simulation, which revealed stable interactions based on root mean square deviation/fluctuation (RMSD/RMSF), radius of gyration, Gibbs free energy landscapes, and principal component analyses (PCA). Moreover, the ADME properties of the compounds align with Lipinski’s rule of five, suggesting their potential as viable candidates for the development of therapies against inflammatory diseases. All compounds tested inhibited PLA2 more than proteinase K. However, compounds 4b and 4f better inhibited phospholipase A2, whereas compounds 4c and 4d showed better activity against proteinase K.

中文翻译：

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1,2,3,4-四氢嘧啶-5-甲腈衍生物PLA2和蛋白酶K抑制剂的绿色合成、密度泛函理论（DFT）、分子对接、分子动力学模拟及生物活性

在动脉粥样硬化、类风湿性关节炎和败血症等疾病中，磷脂酶 A2 (PLA2) 和蛋白酶 K 通过释放花生四烯酸 (AA) 在炎症中发挥作用。据信，炎症过程中的关键步骤是 PLA2 动员 AA 后前列腺素的释放。阻碍花生四烯酸级联中 COX 和 LOX 途径的药物，抑制这些酶的药物可以治疗炎症过程。为了对抗这些炎症促进剂，作者在此报道了一种在乙醇中以 TiO2 为光催化剂的作用下合成一系列 1,2,3,4-四氢嘧啶-5-甲腈衍生物 (4a–h) 的有效方法。培养基，并评估了它们对磷脂酶 A2 以及蛋白酶 K 的作用。结果证实，使用 TiO (20 mg) 作为光催化剂在产率和反应时间方面表现出优异的性能。在短短 60 分钟内，所有合成化合物的收率在 79% 至 91% 之间。仔细评估所检测的化合物对两种酶的 SAR 后，发现具有供电子取代基的化合物 (4b, 4f) 比具有移电子取代基的化合物 (4a, 4e) 具有更高的 PLA2 抑制活性 (%)。与其他给电子或吸电子化合物相比，含有杂环的化合物（4c，4d）表现出显着更高的蛋白酶抑制（％）活性。进一步证实，针对这两种酶的研究化合物表现出剂量依赖性行为。我们通过与人非胰腺分泌磷脂酶 A2 和蛋白酶 K 的分子对接研究了化合物的分子间相互作用。我们使用 100 ns 分子动力学模拟评估了对接复合物的动态稳定性，该模拟揭示了基于均方根偏差的稳定相互作用/波动 (RMSD/RMSF)、回转半径、吉布斯自由能图和主成分分析 (PCA)。此外，这些化合物的 ADME 特性符合 Lipinski 的五法则，表明它们具有作为开发炎症性疾病疗法的可行候选者的潜力。所有测试的化合物对 PLA2 的抑制作用均强于蛋白酶 K。然而，化合物 4b 和 4f 更好地抑制磷脂酶 A2，而化合物 4c 和 4d 对蛋白酶 K 表现出更好的活性。