Department of Pharmaceutical Chemistry, Vivekananda College of Pharmacy, Rajiv Gandhi University of Health Sciences, Bangalore, India.
Department of Pharmaceutical Chemistry, KLE University's College of Pharmacy, Bangalore, India.
Arch Pharm (Weinheim). 2018 Jun;351(6):e1800030. doi: 10.1002/ardp.201800030. Epub 2018 May 7.
A new series of 4-((5-fluoro-6-(substituted)-1H-benzo[d]imidazol-2-ylthio)methyl)-benzoic acids 4a-o and 2-(5-fluoro-6-(substituted)-1H-benzo[d]imidazol-2-ylthio)-2-methylpropanoic acids 8a-e were synthesized, and their inhibitory potencies against soluble epoxide hydrolase (sEH) and 5-lipoxygenase (5-LOX) were investigated. These molecules were designed based on the combination of 5-LOX and sEH pharmacophores, resulting in hybrid analogs with potent sEH and 5-LOX inhibitory activity. Compound 4g showed remarkable activity with IC values of less than 1 μM (0.9 μM) against 5-LOX, while compound 4k displayed promising activity against sEH with IC ≤ 1 μM (0.7 μM). These compounds were evaluated for their in vivo potential using the carrageenan-induced rat paw edema assay. Based on the obtained results, the structure-activity relationship was established and a correlation between the activities was observed. Compounds 4f, 4g, 4k, 4n, and 8e showed potent anti-inflammatory activity and significant inhibition of edema (64.13, 67.39, 66.30, 65.21, and 58.69%, respectively) at a dose of 100 mg/kg, comparable to the standard drug ibuprofen (70.65%) at 3 h.
合成了一系列新的 4-((5-氟-6-(取代)-1H-苯并[d]咪唑-2-基硫代)甲基)苯甲酸 4a-o 和 2-(5-氟-6-(取代)-1H-苯并[d]咪唑-2-基硫代)-2-甲基丙氨酸 8a-e，并研究了它们对可溶性环氧化物水解酶 (sEH) 和 5-脂氧合酶 (5-LOX) 的抑制活性。这些分子是基于 5-LOX 和 sEH 药效团的结合设计的，导致具有强效 sEH 和 5-LOX 抑制活性的混合类似物。化合物 4g 对 5-LOX 的抑制活性非常显著，IC 值低于 1μM(0.9μM)，而化合物 4k 对 sEH 的抑制活性也很有前景，IC 值 ≤ 1μM(0.7μM)。这些化合物在角叉菜胶诱导的大鼠足肿胀试验中进行了体内潜力评估。根据获得的结果，建立了构效关系，并观察到了活性之间的相关性。化合物 4f、4g、4k、4n 和 8e 在 100mg/kg 剂量下表现出很强的抗炎活性和显著的水肿抑制作用(分别为 64.13%、67.39%、66.30%、65.21%和 58.69%），与标准药物布洛芬(70.65%)在 3 小时时相当。
