Based on the significant anti-inflammatory activity of natural quinone primin (5a), series of 1,4-benzoquinones, hydroquinones, and related resorcinols were designed, synthesized, characterized and tested for their ability to inhibit the activity of cyclooxygenase (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) enzymes. Structural modifications resulted in the identification of two compounds 5b (2-methoxy-6-undecyl-1,4-benzoquinone) and 6b (2-methoxy-6-undecyl-1,4-hydroquinone) as potent dual COX/5-LOX inhibitors. The IC₅₀ values evaluated in vitro using enzymatic assay were for compound 5b IC₅₀ = 1.07, 0.57, and 0.34 μM and for compound 6b IC₅₀ = 1.07, 0.55, and 0.28 μM for COX-1, COX-2, and 5-LOX enzyme, respectively. In addition, compound 6d was identified as the most potent 5-LOX inhibitor (IC₅₀ = 0.14 μM; reference inhibitor zileuton IC₅₀ = 0.66 μM) from the tested compounds while its inhibitory potential against COX enzymes (IC₅₀ = 2.65 and 2.71 μM for COX-1 and COX-2, respectively) was comparable with the reference inhibitor ibuprofen (IC₅₀ = 4.50 and 2.46 μM, respectively). The most important structural modification leading to increased inhibitory activity towards both COXs and 5-LOX was the elongation of alkyl chain in position 6 from 5 to 11 carbons. Moreover, the monoacetylation in ortho position of bromo-hydroquinone 13 led to the discovery of potent (IC₅₀ = 0.17 μM) 5-LOX inhibitor 17 (2-bromo-6-methoxy-1,4-benzoquinone) while bromination stabilized the hydroquinone form. Docking analysis revealed the interaction of compounds with Tyr355 and Arg120 in the catalytic site of COX enzymes, while the hydrophobic parts of the molecules filled the hydrophobic substrate channel leading up to Tyr385. In the allosteric catalytic site of 5-LOX, compounds bound to Tyr142 and formed aromatic interactions with Arg138. Taken together, we identified optimal alkyl chain length for dual COX/5-LOX inhibition and investigated other structural modifications influencing COX and 5-LOX inhibitory activity.

基于天然醌primin（5a）的显着抗炎活性，设计，合成，表征和测试了一系列1,4-苯醌，对苯二酚和相关间苯二酚抑制环氧化酶（COX-1）的能力。和COX-2）和5-脂氧合酶（5-LOX）酶。结构修饰导致鉴定出两种化合物5b（2-甲氧基-6-十一烷基-1,4-苯醌）和6b（2-甲氧基-6-十一烷基-1,4-氢醌）作为有效的双重COX / 5-LOX抑制剂。使用酶促测定在体外评估的IC ₅₀值对于化合物5b为IC ₅₀ = 1.07、0.57和0.34μM，对于化合物6b对于COX-1，COX-2和5-LOX酶，IC _50分别为1.07、0.55和0.28μM。此外，化合物6d被鉴定为测试化合物中最有效的5-LOX抑制剂（IC ₅₀ = 0.14μM；参考抑制剂齐留通IC ₅₀ = 0.66μM），而其对COX酶的抑制潜力（IC ₅₀ = 2.65和2.71μM对于COX-1和COX-2的浓度分别与参考抑制剂布洛芬（IC ₅₀分别为4.50和2.46μM）。导致对COX和5-LOX抑制活性增强的最重要的结构修饰是6位烷基链从5个碳原子延长到11个碳原子。此外，溴对苯二酚13在邻位的单乙酰化导致发现有效的（IC ₅₀ = 0.17μM）5-LOX抑制剂17（2-溴-6-甲氧基-1,4-苯醌），而溴化稳定了对苯二酚的形式。对接分析揭示了化合物与Tyr355和Arg120在COX酶催化位点之间的相互作用，而分子的疏水部分填充了导致Tyr385的疏水底物通道。在5-LOX的变构催化位点，化合物与Tyr142结合并与Arg138形成芳族相互作用。总之，我们确定了双重COX / 5-LOX抑制的最佳烷基链长度，并研究了影响COX和5-LOX抑制活性的其他结构修饰。