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

GÜR MAZ Z. T., ÇALIŞKAN B., Garscha U., OLĞAÇ A., Schubert U. S., Gerstmeier J., ...Daha Fazla

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, cilt.150, ss.876-899, 2018 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 150
  • Basım Tarihi: 2018
  • Doi Numarası: 10.1016/j.ejmech.2018.03.045
  • Dergi Adı: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.876-899
  • Anahtar Kelimeler: 5-Lipoxygenase-activating protein, 5-Lipoxygenase, Microsomal prostaglandin E-2 synthase-1, Leukotriene, Benzimidazole, Inflammation, 5-LIPOXYGENASE-ACTIVATING PROTEIN FLAP, ARACHIDONIC-ACID, INFLAMMATORY DISEASES, BIOLOGICAL EVALUATION, C-4 SYNTHASE, IN-VIVO, LICOFELONE, MPGES-1, POTENT, DESIGN
  • Gazi Üniversitesi Adresli: Evet

Özet

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.