Structures of Zileuton, Representative Dual COX-2/5-LOX inhibitors and Lead Compound 1

January 03, 2024

• Title:

  Structures of Zileuton, Representative Dual COX-2/5-LOX inhibitors and Lead Compound 1

• Image Source:

  Discovery of potential anti-inflammatory drugs: Diaryl-1,2,4-triazoles bearing N-hydroxyurea moiety as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase

• Mark:

  Fig 1

• Associated context:

  we have reported that 1,5-diaryl-1,2,4-triazole  derivatives were identified as selective COX-2 inhibitors,  among which compound 1 exhibited potent and selective  COX-2 inhibitory activity (IC50 = 0.37 μM, SI = 0.018), being  equipotent to celecoxib.31 Meanwhile we have noticed a report  about hydroxamic acid or N-hydroxyurea structures, which have  provided one of the most successful strategies to develop iron-  chelating 5-LOX inhibitors—zileuton (Fig. 1).32 As a part of our  continuing effort to find new NSAIDs candidates, we became  interested in exploring dual COX-2/5-LOX inhibitors with novel  structural characteristics, better anti-inflammatory effects and  lower cardiovascular risk. Accordingly, we designed a series of  novel hybrids in which the selective inhibitory COX-2 moiety  diaryl-1,2,4-triazole of compound 1 was incorporated with  hydroxamic acid or N-hydroxyurea group. Herein we report the  synthesis, biological evaluation and docking studies of these  diaryl-1,2,4-triazoles bearing the hydroxamic acid or hydro-  xyurea moiety as dual COX/5-LOX inhibitors (Fig. 2).