Identification of multi-target inhibitors of leukotriene and prostaglandin E-2 biosynthesis by structural tuning of the FLAP inhibitor BRP-7

Leukotrienes (LTs) and prostaglandin (PG)E-2 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 (HAP) and microsomal prostaglandin E-2 synthase (mPGES)-1 in LT and PGE(2) biosynthesis, based on the previously identified selective FLAP inhibitor BRP-7 (8, IC50 = 0.31 mu M). 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 mu M) by targeting FLAP along with inhibition of mPGES-1 (IC50 = 0.42 mu M). 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 mu M) 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 PGE(2) production. (C) 2018 Elsevier Masson SAS. All rights reserved.