Substituted 1,2,4-Triazoles as Novel and Selective Inhibitors of Leukotriene Biosynthesis Targeting 5-Lipoxygenase-Activating Protein

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Olğaç A., Çapan İ., Dahlke P., Jordan P. M., Werz O., Banoglu E.

ACS OMEGA, cilt.8, sa.34, ss.31293-31304, 2023 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 8 Sayı: 34
  • Basım Tarihi: 2023
  • Doi Numarası: 10.1021/acsomega.3c03682
  • Dergi Adı: ACS OMEGA
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Directory of Open Access Journals
  • Sayfa Sayıları: ss.31293-31304
  • Gazi Üniversitesi Adresli: Evet

Özet

5-Lipoxygenase-activating protein (FLAP) is a regulatorof cellularleukotriene biosynthesis, which governs the transfer of arachidonicacid (AA) to 5-lipoxygenase for efficient metabolism. Here, the synthesisand FLAP-antagonistic potential of fast synthetically accessible 1,2,4-triazolederivatives based on a previously discovered virtual screening hitcompound is described. Our findings reveal that simple structuralvariations on 4,5-diaryl moieties and the 3-thioether side chain ofthe 1,2,4-triazole scaffold markedly influence the inhibitory potential,highlighting the significant chemical features necessary for FLAPantagonism. Comprehensive metabololipidomics analysis in activatedFLAP-expressing human innate immune cells and human whole blood showedthat the most potent analogue 6x selectively suppressedleukotriene B-4 formation evoked by bacterial exotoxinswithout affecting other branches of the AA pathway. Taken together,the 1,2,4-triazole scaffold is a novel chemical platform for the developmentof more potent FLAP antagonists, which warrants further explorationfor their potential as a new class of anti-inflammatory agents.