School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China.
Bioorg Med Chem. 2020 Jun 1;28(11):115526. doi: 10.1016/j.bmc.2020.115526. Epub 2020 Apr 22.
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. LD 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 PGE level significantly. In summary, 1,3-benzothiazinone derivatives are unique scaffolds with anti-inflammatory activity and low toxicity.
设计并合成了一系列 1,3-苯并噻嗪酮衍生物，用于药理学评估。在所合成的 19 种化合物中，一些化合物在抑制 LPS 诱导的一氧化氮和 TNF-α产生、下调 COX-2 和增加 RAW264.7 细胞中 IL-10 产生方面表现出很高的活性。所有化合物在体外试验中均无明显的细胞毒性。化合物 25 的 LD 值大于 2000mg/kg，比美洛昔康更安全。化合物 25 显著抑制 LPS 诱导的 RAW264.7 细胞中 NF-κB 和 STAT3 的磷酸化。与美洛昔康相比，合成化合物对 COX 活性的抑制作用较弱。化合物 25 显示出比美洛昔康更低的胃肠道毒性。此外，化合物 25 可降低角叉菜胶诱导的炎症性足肿胀模型中的肿胀程度，并显著降低 PGE 水平。总之，1,3-苯并噻嗪酮衍生物是具有抗炎活性和低毒性的独特支架。
