Synthesis and biological evaluation of isoxazolo[4,5-d]pyridazin-4-(5H)-one analogues as potent anti-inflammatory agents


Ozadali K., ÖZKANLI F., Jain S., Rao P. P. N. , Velazquez-Martinez C. A.

BIOORGANIC & MEDICINAL CHEMISTRY, vol.20, no.9, pp.2912-2922, 2012 (Peer-Reviewed Journal) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 20 Issue: 9
  • Publication Date: 2012
  • Doi Number: 10.1016/j.bmc.2012.03.021
  • Journal Name: BIOORGANIC & MEDICINAL CHEMISTRY
  • Journal Indexes: Science Citation Index Expanded, Scopus
  • Page Numbers: pp.2912-2922

Abstract

In this study, eighteen new isoxazolo[4,5-d]pyridazin-4(5H)-one derivatives possessing either a 1,3,4-thiadiazole or a 1,2,4-triazole-5-thione moiety were synthesized and tested for anti-inflammatory activity in vitro (COX-1/COX-2, 5-LOX) and in vivo (rat paw edema assay). Compounds 15, 16, 25, 26 and 28–30 showed dual COX-2 (IC50’s in the 2.1–10.9 lM range), and 5-LOX (IC50’s in the 6.3–63.5 lM range) inhibitory activity. When administered orally to rats, dual COX-2/5-LOX inhibitors showed higher antiinflammatory activity in vivo (30–45% reduction of the inflammatory response) than the reference drug ibuprofen (18%). Among dual COX-2/5-LOX inhibitors, the most potent compound (28) exhibited the best anti-inflammatory profile by inhibiting both COX-2 (IC50 = 2.1 lM) and 5-LOX (IC50 = 6.3 lM) enzymes. We investigated the binding interactions of compound 28 by an enzyme–ligand molecular modeling (docking) studies, which showed favorable binding interactions in both COX-2 and 5-LOX active sites. Furthermore, the dual acting COX-2/5-LOX compound 28 exhibited a superior gastrointestinal safety profile (ulcer index = 0.25) compared to the reference drug ibuprofen (UI = 7.0) when administered orally at the same molar dose. These observations suggest that isoxazolo[4,5-d]pyridazin-4(5H)-one analogs represent a new scaffold to design potent, effective, and safe anti-inflammatory agents possessing dual COX-2/5-LOX inhibitory activity.

In this study, eighteen new isoxazolo[4,5-d]pyridazin-4(5H)-one derivatives possessing either a 1,3,4-thiadiazole or a 1,2,4-triazole-5-thione moiety were synthesized and tested for anti-inflammatory activity in vitro (COX-1/COX-2, 5-LOX) and in vivo (rat paw edema assay). Compounds 15, 16, 25, 26 and 28-30 showed dual COX-2 (IC50's in the 2.1-10.9 mu M range), and 5-LOX (IC50's in the 6.3-63.5 mu M range) inhibitory activity. When administered orally to rats, dual COX-2/5-LOX inhibitors showed higher anti-inflammatory activity in vivo (30-45% reduction of the inflammatory response) than the reference drug ibuprofen (18%). Among dual COX-2/5-LOX inhibitors, the most potent compound (28) exhibited the best anti-inflammatory profile by inhibiting both COX-2 (IC50 = 2.1 mu M) and 5-LOX (IC50 = 6.3 mu M) enzymes. We investigated the binding interactions of compound 28 by an enzyme-ligand molecular modeling (docking) studies, which showed favorable binding interactions in both COX-2 and 5-LOX active sites. Furthermore, the dual acting COX-2/5-LOX compound 28 exhibited a superior gastrointestinal safety profile (ulcer index = 0.25) compared to the reference drug ibuprofen (UI = 7.0) when administered orally at the same molar dose. These observations suggest that isoxazolo[4,5-d]pyridazin-4(5H)-one analogs represent a new scaffold to design potent, effective, and safe anti-inflammatory agents possessing dual COX-2/5-LOX inhibitory activity. (C) 2012 Elsevier Ltd. All rights reserved.