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

Junfang Li; Xiaohong Fan; Jiedan Deng; Yan Liang; Shumeng Ma; Yingmei Lu; Jian Zhang; Tao Shi; Wen Tan; Zhen Wang

doi:10.1016/j.bmc.2020.115526

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.

Authors

Junfang Li¹, Xiaohong Fan¹, Jiedan Deng¹, Yan Liang¹, Shumeng Ma¹, Yingmei Lu¹, Jian Zhang², Tao Shi³, Wen Tan⁴, Zhen Wang⁵

Affiliations

¹ School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
² School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China.
³ School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: shit18@lzu.edu.cn.
⁴ School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: tanwen@lzu.edu.cn.
⁵ School of Pharmacy, Lanzhou University, Lanzhou 730000, China; State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China. Electronic address: zhenw@lzu.edu.cn.

PMID: 32354672
DOI: 10.1016/j.bmc.2020.115526

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