Leukotrienes (LTs) and prostaglandin (PG)E₂ are enzymatically produced from arachidonic acid and represent highly bioactive lipid mediators with pro-inflammatory functions. Here, we report on novel multi-target inhibitors that potently and dually interfere with 5-lipoxygenase-activating protein (FLAP) and microsomal prostaglandin E₂ synthase (mPGES)-1 in LT and PGE₂ biosynthesis, based on the previously identified selective FLAP inhibitor BRP-7 (8, IC₅₀ = 0.31 μM). C (5)-substitution of the benzimidazole ring of BRP-7 by carboxylic acid and its bioisosteres provided compounds, exemplified by 57 that potently suppress LT formation (IC₅₀ = 0.05 μM) by targeting FLAP along with inhibition of mPGES-1 (IC₅₀ = 0.42 μM). Besides FLAP, also 5-lipoxygenase (5-LO) and LTC₄ synthase activities were inhibited by 57, albeit with lower potency (IC₅₀ = 0.6 and 6.2 μM) than FLAP. Docking studies and molecular dynamic simulations with FLAP, mPGES-1 and 5-LO provide valuable insights into potential binding interactions of the inhibitors with their targets. Together, these novel benzimidazole derivatives may possess potential as leads for development of effective anti-inflammatory drugs with multi-target properties for dually inhibiting LT and PGE₂ production.

白三烯（LTs）和前列腺素（PG）E ₂由花生四烯酸酶促生产，代表具有促炎功能的高生物活性脂质介体。在这里，我们基于先前确定的选择性FLAP ，报道了在LT和PGE ₂生物合成中有力和双重干扰5-脂氧合酶激活蛋白（FLAP）和微粒体前列腺素E ₂合酶（mPGES）-1的新型多靶标抑制剂抑制剂BRP-7（8，IC ₅₀  = 0.31μM）。C（5）取代BRP-7的苯并咪唑环的羧酸及其生物等排体提供的化合物，例如57可以有效抑制LT形成的化合物（IC ₅₀ 靶向FLAP并抑制mPGES-1（IC ₅₀  = 0.42μM），从而获得= 0.05μM ）。除FLAP以外，5-脂氧合酶（5-LO）和LTC ₄合酶活性也被57抑制，尽管其效力（IC ₅₀  = 0.6和6.2μM）比FLAP低。用FLAP，mPGES-1和5-LO进行的对接研究和分子动力学模拟为抑制剂与靶标之间的潜在结合相互作用提供了宝贵的见解。这些新的苯并咪唑衍生物一起可能具有潜在的潜力，可作为开发具有双重抑制LT和PGE ₂产生的多靶点性质的有效抗炎药的先导。