Design and synthesis of 1,3-benzothiazinone derivatives as potential anti-inflammatory agents

Bioorg Med Chem. 2020 Jun 1;28(11):115526. doi: 10.1016/j.bmc.2020.115526. Epub 2020 Apr 22.

Abstract

A series of 1,3-benzothiazinone derivatives were designed and synthesized for pharmacological assessments. Among the synthesized 19 compounds, some compounds showed high activities on inhibiting LPS-induced nitrite oxide and TNF-α production, down-regulating COX-2 and increasing IL-10 production in RAW264.7 cells. All the compounds had no obvious cytotoxicity in in vitro assay. LD50 value of compound 25 was greater than 2000 mg/kg, which was safer than meloxicam. Compound 25 significantly inhibited phosphorylation of NF-κB and STAT3 in LPS-induced RAW264.7 cells. Inhibition of synthesized compounds on COX activity was weaker than meloxicam. Compound 25 displayed lower gastrointestinal toxicity than meloxicam. Besides, compound 25 decreased the swelling in carrageenan-induced paw edema models of inflammation and reduced PGE2 level significantly. In summary, 1,3-benzothiazinone derivatives are unique scaffolds with anti-inflammatory activity and low toxicity.

Keywords: 1,3-benzothiazinone; Anti-inflammatory; Meloxicam; Toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Carrageenan
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Edema / chemically induced
  • Edema / drug therapy*
  • Edema / pathology
  • Inflammation / chemically induced
  • Inflammation / drug therapy*
  • Inflammation / pathology
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Mice
  • Molecular Structure
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Nitric Oxide / antagonists & inhibitors
  • Nitric Oxide / biosynthesis
  • Phosphorylation / drug effects
  • RAW 264.7 Cells
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / metabolism
  • Structure-Activity Relationship
  • Thiazines / chemical synthesis
  • Thiazines / chemistry
  • Thiazines / pharmacology*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Lipopolysaccharides
  • NF-kappa B
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Thiazines
  • Nitric Oxide
  • Carrageenan