Identification of novel benzimidazole derivatives as inhibitors of leukotriene biosynthesis by virtual screening targeting 5-lipoxygenase-activating protein (FLAP)

BANOĞLU E., ÇALIŞKAN B., Luderer S., EREN G., Ozkan Y., Altenhofen W., ...Daha Fazla

BIOORGANIC & MEDICINAL CHEMISTRY, cilt.20, sa.12, ss.3728-3741, 2012 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 20 Sayı: 12
  • Basım Tarihi: 2012
  • Doi Numarası: 10.1016/j.bmc.2012.04.048
  • Dergi Adı: BIOORGANIC & MEDICINAL CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.3728-3741
  • Anahtar Kelimeler: 5-Lipoxygenase, Leukotriene, Inflammation, Neutrophils, INFLAMMATORY DISEASES, ACTIVATING PROTEIN, POTENT, ASTHMA
  • Gazi Üniversitesi Adresli: Evet

Özet

Pharmacological suppression of leukotriene biosynthesis by 5-lipoxygenase (5-LO)-activating protein (FLAP) inhibitors is a promising strategy to intervene with inflammatory, allergic and cardiovascular diseases. Virtual screening targeting FLAP based on a combined ligand-and structure-based pharmacophore model led to the identification of 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl)ethyl)-1H-benzimidazole (7) as developable candidate. Compound 7 potently suppressed leukotriene formation in intact neutrophils (IC50 = 0.31 mu M) but essentially failed to directly inhibit 5-LO suggesting that interaction with FLAP causes inhibition of leukotriene synthesis. For structural optimization, a series of 46 benzimidazole-based derivatives of 7 were synthesized leading to more potent analogues (70-72, 82) with IC50 = 0.12-0.19 mu M in intact neutrophils. Together, our results disclose the benzimidazole scaffold bearing an ibuprofen fingerprint as a new chemotype for further development of anti-leukotriene agents. (C) 2012 Elsevier Ltd. All rights reserved.