Design, synthesis and biological evaluation of alantolactone derivatives as potential anti-inflammatory agents

  • Chetan Kumar
  • Anil Kumar
  • Yedukondalu Nalli
  • Waseem I. Lone
  • Naresh K. Satti
  • M. K. Verma
  • Zabeer Ahmed
  • Asif AliEmail author
Original Research


While screening for potential anti-inflammatory natural product scaffolds, alantolactone (1) was found to attenuate LPS-induced pro-inflammatory mediators in RAW264.7 macrophage cells. In this regard, a series of 17 novel thiol derivatives of 1 has been synthesized and evaluated as inhibitors of pro-inflammatory mediators viz. NO (nitric oxide), IL-6 (interleukin-6), and TNF-α (tumor necrosis factor-α) in LPS-treated RAW264.7 macrophage cells (In vitro) and female Balb/C mice (in vivo). In vitro, the best inhibition potencies were obtained with compounds 3, 4, 6, and 18, which were selected for further in vivo testing. The results of in vivo studies revealed that compounds 3, 6, and 18 are comparable to that of the parent molecule 1 on the inhibition of TNF-α and IL-6 release, whereas compound 4 was identified as the most potent inhibitor of cytokines IL-6 (69.49%) and TNF-α (66.12%) as compared with 1 at dose 10 mg/kg. Taken together, our results suggest that thiol analogs of 1 have therapeutic potential and could be further explored for potential anti-inflammatory activity.


Inula racemosa Alantolactone Thiol derivatives Anti-inflammatory activities 



CK and AK acknowledge AcSIR for their enrollment in PhD program. We would like to acknowledge the Ministry of AYUSH (New Delhi) for providing financial support for the work of Y. K (Z.28015/229/2015-HCP EMR). The article bears the institutional manuscript no. IIIM/2281/2019.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2019_2337_MOESM1_ESM.docx (15.5 mb)
Supporting Information


  1. Cantrell CL, Abate L, Fronczek FR, Franzblau SG, Quijano L, Fischer NH (1999) Antimycobacterial eudesmanolides from Inula helenium and Rudbeckia subtomentosa. Planta Med 65:351–355CrossRefGoogle Scholar
  2. Chun J, Choi RJ, Khan S, Lee DS, Kim YC, Nam YJ, Lee DU, Kim YS (2012) Alantolactone suppresses inducible nitric oxide synthase and cyclooxygenase-2 expression by down-regulating NF-kappaB, MAPK and AP-1 via the MyD88 signaling pathway in LPS-activated RAW 264.7 cells. Int Immunopharmacol 14:375–383CrossRefGoogle Scholar
  3. Gao S, Wang Q, Tian X-H, Li H-L, Shen Y-H, Xu X-K, Wu G-Z, Hu Z-L, Zhang W-D (2017) Total sesquiterpene lactones prepared from Inula helenium L. has potentials in prevention and therapy of rheumatoid arthritis. J Ethnopharmacol 196:39–46CrossRefGoogle Scholar
  4. Gupta S, Khajuria V, Wani A, Nalli Y, Bhagat A, Ali A, Ahmed Z (2018) Murrayanine attenuates lipopolysaccharide-induced inflammation and protects mice from sepsis-associated organ failure. Basic Clin Pharmacol Toxicol.
  5. Lim HS, Jin SE, Kim OS, Shin HK, Jeong SJ (2015) Alantolactone from Saussurea lappa exerts antiinflammatory effects by inhibiting chemokine production and STAT1 phosphorylation in TNF-α and IFN-gamma-induced in HaCaT cells. Phytother Res 29:1088–1096CrossRefGoogle Scholar
  6. Ma Y-Y, Zhao D-G, Gao K (2013) Structural investigation and biological activity of sesquiterpene lactones from the traditional chinese herb Inula racemosa. J Nat Prod 76:564–570CrossRefGoogle Scholar
  7. Maryam A, Mehmood T, Zhang H, Li Y, Khan M, Ma T (2017) Alantolactone induces apoptosis, promotes STAT3 glutathionylation and enhances chemosensitivity of A549 lung adenocarcinoma cells to doxorubicin via oxidative stress. Sci Rep 7:6242CrossRefGoogle Scholar
  8. Nalli Y, Gupta S, Khajuria V, Singh VP, Sajgotra M, Ahmed Z, Thakur NL, Ali A (2017) TNF-α and IL-6 inhibitory effects of cyclic dipeptides isolated from marine bacteria Streptomyces sp. Med Chem Res 26:93–100CrossRefGoogle Scholar
  9. Nalli Y, Khajuria V, Gupta S, Arora P, Riyaz-Ul-Hassan S, Ahmed Z, Ali A (2016) Four new carbazole alkaloids from Murraya koenigii that display anti-inflammatory and anti-microbial activities. Org Biomol Chem 14:3322–3332CrossRefGoogle Scholar
  10. Picman AK, Schneider EF (1993) Inhibition of fungal growth by selected sesquiterpene lactones. Biochem Syst Ecol 21:307–314CrossRefGoogle Scholar
  11. Seca AM, Grigore A, Pinto DC, Silva AM (2014) The genus Inula and their metabolites: from ethnopharmacological to medicinal uses. J Ethnopharmacol 154:286–310CrossRefGoogle Scholar
  12. Seo JY, Lim SS, Kim JR, Lim JS, Ha YR, Lee IA, Kim EJ, Park JH, Kim JS (2008) Nrf2-mediated induction of detoxifying enzymes by alantolactone present in Inula helenium. Phytother Res 22:1500–1505CrossRefGoogle Scholar
  13. Wang X, Yu Z, Wang C, Cheng W, Tian X, Huo X, Wang Y, Sun C, Feng L, Xing J, Lan Y, Sun D, Hou Q, Zhang B, Ma X, Zhang B (2017) Alantolactone, a natural sesquiterpene lactone, has potent antitumor activity against glioblastoma by targeting IKKβ kinase activity and interrupting NF-κB/COX-2-mediated signaling cascades. J Exp Clin Cancer Res: CR 36:93CrossRefGoogle Scholar
  14. Yuliya P, Bakhtiyor R, Vladimir S, Zainab K, Jerzy L (2009) Structure‐hepatoprotective activity relationship study of sesquiterpene lactones: a QSAR analysis. Int J Quantum Chem 109:17–27CrossRefGoogle Scholar
  15. Zhao P, Pan Z, Luo Y, Zhang L, Li X, Zhang G, Zhang Y, Cui R, Sun M, Zhang X (2015) Alantolactone induces apoptosis and cell cycle arrest on lung squamous cancer SK-MES-1 cells. J Biochem Mol Toxicol 29:199–206CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Natural Products Chemistry DivisionCSIR-Indian Institute of Integrative MedicineJammuIndia
  2. 2.Academy of Scientific & Innovative Research (AcSIR)Anusandhan BhawanNew DelhiIndia
  3. 3.Inflammation Pharmacology DivisionCSIR-Indian Institute of Integrative MedicineJammu-TawiIndia

Personalised recommendations