Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
Molecules. 2023 Dec 5;28(24):7958. doi: 10.3390/molecules28247958.
Molecular hybridization has emerged as a promising approach in the treatment of diseases exhibiting multifactorial etiology. With regard to this, dual cyclooxygenase-2/lipoxygenase (COX-2/LOX) inhibitors could be considered a safe alternative to traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs) for the treatment of inflammatory conditions. Taking this into account, six novel pyrrole derivatives and pyrrole-cinnamate hybrids were developed as potential COX-2 and soybean LOX (sLOX) inhibitors with antioxidant activity. In silico calculations were performed to predict their ADMET (absorption, distribution, metabolism, excretion, toxicity) properties and drug-likeness, while lipophilicity was experimentally determined as R values. All synthesized compounds (-, -) could be described as drug-like. The results from the docking studies on COX-2 were in accordance with the in vitro studies. According to molecular docking studies on soybean LOX, the compounds displayed allosteric interactions with the enzyme. Pyrrole appeared to be the most potent s-LOX inhibitor (IC = 7.5 μM). Hybrids and presented a promising combination of in vitro LOX (IC for = 30 μM, IC for = 27.5 μM) and COX-2 (IC for = 0.55 μM, IC for = 7.0 μM) inhibitory activities, and therefore could be used as the lead compounds for the synthesis of more effective multi-target agents.
分子杂交已成为治疗多病因疾病的一种有前途的方法。在这方面，双环氧化酶-2/脂氧合酶（COX-2/LOX）抑制剂可以被认为是传统非甾体抗炎药（tNSAIDs）和选择性 COX-2 抑制剂（coxibs）的安全替代品，用于治疗炎症性疾病。考虑到这一点，我们开发了六种新型吡咯衍生物和吡咯肉桂酰胺杂合体，作为具有抗氧化活性的潜在 COX-2 和大豆脂氧合酶（sLOX）抑制剂。进行了计算机模拟计算以预测它们的 ADMET（吸收、分布、代谢、排泄、毒性）特性和类药性，而亲脂性则通过 R 值实验确定。所有合成的化合物（-，-）都可以被描述为类药性。COX-2 对接研究的结果与体外研究一致。根据对大豆脂氧合酶的分子对接研究，这些化合物与酶显示出变构相互作用。吡咯似乎是最有效的 s-LOX 抑制剂（IC = 7.5 μM）。杂合体和表现出体外 LOX（IC 对于 = 30 μM，IC 对于 = 27.5 μM）和 COX-2（IC 对于 = 0.55 μM，IC 对于 = 7.0 μM）抑制活性的有希望的组合，因此可以用作合成更有效的多靶标药物的先导化合物。
