Abstract

Lipoxygenases (LOXs) are a group of enzymes that catalyze the oxidation of polyunsaturated fatty acids and initiate the biosynthesis of secondary metabolites that are involved to control inflammation. In search of new and more potent LOX inhibitors, a series of new 3-(5-(4-chlorophenyl)-4-(2-furylmethyl)-1,2,4-triazole hybrids was prepared and screened for its LOX inhibitory potential. 4-Chlorobenzoic acid (a) was metamorphosed into N-furfuryl-5-(4-chlorophenyl)-4-(2-furylmethyl)-1,2,4-triazole (4) via intermediates like benzoate (1), hydrazide (2) and semicarbazide (3). Finally, triazole (4) was fused with propionamides (6a–o) and transformed it into the aimed derivatives (7a–o). The structural interpretations of the prepared derivatives (7a–o) were accomplished via FTIR, ¹H-, ¹³C-NMR spectroscopy, EI-MS and HR-EI-MS spectrometry. The inhibitory potency of the compounds against soybean 15-LOX was determined by in vitro assay using chemiluminescence method. Compounds 7a and 7f exhibited potent LOX inhibitory profiles with IC₅₀ 21.83 ± 0.56 and 25.72 ± 0.51 µM, whereas 7d and 7e showed comparable inhibitory potential with IC₅₀ values of 34.52 ± 0.39 and 39.12 ± 0.46 µM, respectively. Compounds 7a, 7f, 7d and 7e exhibited 65.58 ± 1.4%, 54.72 ± 1.3%, 58.52 ± 1.2% and 63.56 ± 1.4% blood mononuclear cells viability, respectively. Density functional theory and molecular docking studies further strengthened the studies of the synthesized compounds and these derivatives perceived to be potential ‘lead’ compounds in drug discovery as anti-LOX.

Communicated by Ramaswamy H. Sarma

摘要

脂氧合酶 (LOX) 是一组催化多不饱和脂肪酸氧化并启动参与控制炎症的次级代谢产物生物合成的酶。为了寻找新的、更有效的 LOX 抑制剂，制备了一系列新型 3-(5-(4-氯苯基)-4-(2-呋喃甲基)-1,2,4-三唑杂化物，并筛选了其 LOX 抑制潜力. 4-氯苯甲酸 ( a )通过苯甲酸酯 ( 1 )、酰肼等中间体变质为N -糠基-5-(4-氯苯基)-4-(2-呋喃基甲基)-1,2,4-三唑 ( 4 ) ( 2 ) 和氨基脲 ( 3 )。最后，三唑 ( 4 ) 与丙酰胺 ( 6a–o）并将其转化为目标导数（7a-o）。^{通过 FTIR、 1} H-、¹³ C-NMR 光谱、EI-MS 和 HR-EI-MS 光谱分析完成了所制备的衍生物 ( 7a-o ) 的结构解释。采用化学发光法体外测定测定化合物对大豆15-LOX的抑制效力。化合物7a和7f表现出有效的 LOX 抑制特性，IC ₅₀为 21.83 ± 0.56 和 25.72 ± 0.51 µM，而7d和7e显示出与 IC _{50相当的抑制潜力}值分别为 34.52 ± 0.39 和 39.12 ± 0.46 µM。化合物7a、7f、7d和7e分别表现出65.58±1.4%、54.72±1.3%、58.52±1.2%和63.56±1.4%血液单核细胞活力。密度泛函理论和分子对接研究进一步加强了对合成化合物和这些衍生物的研究，这些衍生物被认为是抗LOX药物发现中潜在的“先导”化合物。

拉马斯瓦米·萨尔马 (Ramaswamy H. Sarma) 通讯