Department of Chemistry, Baghdad-ul-Jadeed Campus, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan.
Department of Chemistry, Baghdad-ul-Jadeed Campus, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan.
Bioorg Chem. 2021 Feb;107:104525. doi: 10.1016/j.bioorg.2020.104525. Epub 2020 Dec 3.
Hunting small molecules as anti-inflammatory agents/drugs is an expanding and successful approach to treat several inflammatory diseases such as cancer, asthma, arthritis, and psoriasis. Besides other methods, inflammatory diseases can be treated by lipoxygenase inhibitors, which have a profound influence on the development and progression of inflammation. In the present study, a series of new N-alkyl/aralky/aryl derivatives (7a-o) of 2-(4-phenyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)acetamide was synthesized and screened for their inhibitory potential against the enzyme 15-lipoxygenase. The simple precursor ethyl piperidine-4-carboxylate (a) was successively converted into phenylcarbamoyl derivative (1), hydrazide (2), semicarbazide (3) and N-phenylated 5-(1-phenylcarbamoyl)piperidine-1,2,4-triazole (4), then in combination with electrophiles (6a-o) through further multistep synthesis, final products (7a-o) were generated. All the synthesized compounds were characterized by FTIR, H, C NMR spectroscopy, EIMS, and HREIMS spectrometry. Almost all the synthesized compounds showed excellent inhibitory potential against the tested enzyme. Compounds 7c, 7f, 7d, and 7g displayed potent inhibitory potential (IC 9.25 ± 0.26 to 21.82 ± 0.35 µM), followed by the compounds 7n, 7h, 7e, 7a, 7b, 7l, and 7o with IC values in the range of 24.56 ± 0.45 to 46.91 ± 0.57 µM. Compounds 7c, 7f, 7d exhibited 71.5 to 83.5% cellular viability by MTT assay compared with standard curcumin (76.9%) when assayed at 0.125 mM concentration. In silico ADME studies supported the drug-likeness of most of the molecules. In vitro inhibition studies were substantiated by molecular docking wherein the phenyl group attached to the triazole ring was making a π-δ interaction with Leu607. This work reveals the possibility of a synthetic approach of compounds in relation to lipoxygenase inhibition as potential lead compounds in drug discovery.
作为一种治疗多种炎症性疾病（如癌症、哮喘、关节炎和银屑病）的方法，寻找小分子抗炎药物/药物是一种不断发展和成功的方法。除其他方法外，炎症性疾病还可以通过脂氧合酶抑制剂治疗，脂氧合酶抑制剂对炎症的发展和进展有深远的影响。在本研究中，合成了一系列新的 2-（4-苯基-5-（1-苯基氨基甲酰基）哌啶-4H-1,2,4-三唑-3-基硫基）乙酰胺的 N-烷基/芳基/芳基衍生物（7a-o），并对其抑制 15-脂氧合酶的潜力进行了筛选。简单的前体乙基哌啶-4-羧酸酯（a）依次转化为苯甲酰胺衍生物（1）、酰肼（2）、氨基脲（3）和 N-苯基化 5-（1-苯基氨基甲酰基）哌啶-1,2,4-三唑（4），然后通过进一步的多步合成与亲电试剂（6a-o）结合，最终生成产物（7a-o）。所有合成的化合物均通过 FTIR、H、C NMR 光谱、EIMS 和 HREIMS 光谱进行了表征。几乎所有合成的化合物对测试酶均表现出优异的抑制潜力。化合物 7c、7f、7d 和 7g 表现出较强的抑制潜力（IC9.25±0.26 至 21.82±0.35µM），其次是化合物 7n、7h、7e、7a、7b、7l 和 7o，IC 值在 24.56±0.45 至 46.91±0.57µM 范围内。在 0.125mM 浓度下，与标准姜黄素（76.9%）相比，化合物 7c、7f 和 7d 通过 MTT 测定法表现出 71.5%至 83.5%的细胞活力。基于计算机的 ADME 研究支持大多数分子的类药性。体外抑制研究通过分子对接得到了证实，其中连接三唑环的苯基与亮氨酸 607 形成π-δ相互作用。这项工作揭示了与脂氧合酶抑制相关的化合物合成方法的可能性，作为药物发现的潜在先导化合物。
