New synthetic coumarinolignans as attenuators of pro-inflammatory cytokines in LPS-induced sepsis and carrageenan-induced paw oedema models

Santhosh S. Kumar, Kirti Hira, Sajeli Begum Ahil, Onkar P. Kulkarni, Hiroshi Araya, Yoshinori Fujimoto

Research output: Contribution to journalArticlepeer-review


Objectives: The aim of the study was to explore the inhibition efficacy of new synthetic coumarinolignans (SCLs) against the secretion of pro-inflammatory cytokines in two in vivo models of inflammation. Methods: Four SCLs 1–4 were screened for their pro-inflammatory cytokine inhibitory potential through oral administration at a dose of 50 mg/kg body weight in lipopolysaccharide-induced mouse endotoxaemia and carrageenan-induced mouse paw oedema models. Levels of pro-inflammatory cytokines (IL-1β, TNFα and IL-6) in blood and paw tissue samples were estimated using ELISA. Paw oedema was measured using a plethysmometer. Results were compared with a natural coumarinolignan, cleomiscosin A (5), and the structure–activity relationship (SAR) was interpreted. Results and discussion: Compound 2 had the greatest potential in the endotoxaemia model, exhibiting 66.41%, 62.56% and 43.15% inhibition of plasma IL-1β, TNFα and IL-6 secretions, respectively. Further dose-dependent study revealed its anti-inflammatory potential even at dose of 10 mg/kg body weight with 24.42% decline in the level of IL-1β. Nevertheless, SCLs 1, 3 and 4 showed marked inhibitory activity with 57.54%, 51.48% and 62.46% reduction in the levels of IL-1β, respectively. Moreover, compound 2 decreased the plasma TNFα and IL-1β levels to 50.03% and 36.58% along with the reduction of paw oedema volume in the local inflammation induced by carrageenan. All compounds including cleomiscosin A (5) were more effective against IL-1β. By studying SAR, the presence of dihydroxyl groups in the phenyl ring of lignans was identified to be essential for the activity. Also, esterification of lignans and presence of a 4-methyl substituent in the coumarin nucleus were found to play some role in enhancing the activity. Conclusion: All four SCLs, especially compound 2, have shown vast potential to emerge out as promising anti-inflammatory drugs.

Original languageEnglish
Pages (from-to)1365-1373
Number of pages9
Issue number5
Publication statusPublished - 1 Oct 2020


  • Endotoxaemia
  • Paw oedema
  • Pro-inflammatory cytokines
  • Synthetic coumarinolignans

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