Synthesis of Some Novel 2,6-Disubstituted Pyridazin-3(2H)-one Derivatives as Analgesic, Anti-Inflammatory, and Non-Ulcerogenic Agents

Arch Pharm (Weinheim). 2017 Sep;350(9). doi: 10.1002/ardp.201700093. Epub 2017 Aug 9.

Abstract

Some novel 2,6-disubstituted pyridazine-3(2H)-one derivatives were synthesized and evaluated for in vitro cyclooxygenase-2 (COX-2) inhibitory efficacy. Compounds 2-{[3-(2-methylphenoxy)-6-oxopyridazin-1(6H)-yl]methyl}-1H-isoindole-1,3(2H)-dione (5a), 2-propyl-6-(o-tolyloxy)pyridazin-3(2H)-one (6a), and 2-benzyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazin-3(2H)-one (16a) showed the most potent COX-2 inhibitory activity with IC50 values of 0.19, 0.11, and 0.24 μM, respectively. The synthesized compounds with the highest COX-2 selectivity indices were evaluated for their anti-inflammatory, analgesic, and ulcerogenic activities. Compounds 6a and 16a demonstrated the most potent and consistent anti-inflammatory activity over the synthesized compounds, which was significantly higher than that of celecoxib in the carrageenin rat paw edema model and with milder ulcer scoring than that of indomethacin in the ulcerogenicity screening.

Keywords: Analgesic activity; Anti-inflammatory; COX-1; COX-2; Pyridazinone.

MeSH terms

  • Analgesics, Non-Narcotic / chemical synthesis*
  • Analgesics, Non-Narcotic / pharmacology*
  • Analgesics, Non-Narcotic / toxicity
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Anti-Inflammatory Agents, Non-Steroidal / toxicity
  • Cyclooxygenase 2 Inhibitors / chemical synthesis
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Edema / chemically induced
  • Edema / prevention & control
  • Male
  • Pyridazines / chemical synthesis*
  • Pyridazines / pharmacology*
  • Rats
  • Stomach Ulcer / chemically induced*

Substances

  • Analgesics, Non-Narcotic
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase 2 Inhibitors
  • Pyridazines