Standardised comparison of limonene-derived monoterpenes identifies structural determinants of anti-inflammatory activity

Sci Rep. 2020 Apr 29;10(1):7199. doi: 10.1038/s41598-020-64032-1.


Mint species are widely used in traditional and conventional medicine as topical analgesics for osteoarthritic pain and for disorders of the gastrointestinal and respiratory tracts which are all associated with chronic inflammation. To identify the structural determinants of anti-inflammatory activity and potency which are required for chemical optimization towards development of new anti-inflammatory drugs, a selected group of monoterpenes especially abundant in mint species was screened by measuring bacterial lipopolysacharide (LPS)-induced nitric oxide (NO) production in murine macrophages. Nine compounds significantly decreased LPS-induced NO production by more than 30%. IC50 values were calculated showing that the order of potency is: (S)-(+)-carvone > (R)-(-)-carvone > (+)-dihydrocarveol > (S)-8-hydroxycarvotanacetone > (R)-8-hydroxycarvotanacetone > (+)-dihydrocarvone > (-)-carveol > (-)-dihydrocarveol > (S)-(-)-pulegone. Considering the carbon numbering relative to the common precursor, limonene, the presence of an oxygenated group at C6 conjugated to a double bond at C1 and an isopropenyl group and S configuration at C4 are the major chemical features relevant for activity and potency. The most potent compound, (S)-(+)-carvone, significantly decreased the expression of NOS2 and IL-1β in macrophages and in a cell model of osteoarthritis using primary human chondrocytes. (S)-(+)-carvone may be efficient in halting inflammation-related diseases, like osteoarthritis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents* / chemistry
  • Anti-Inflammatory Agents* / pharmacology
  • Chondrocytes / metabolism*
  • Chondrocytes / pathology
  • Humans
  • Limonene* / chemistry
  • Limonene* / pharmacology
  • Lipopolysaccharides / toxicity
  • Mice
  • Models, Biological*
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Osteoarthritis / chemically induced
  • Osteoarthritis / drug therapy*
  • Osteoarthritis / metabolism
  • Osteoarthritis / pathology
  • RAW 264.7 Cells
  • Structure-Activity Relationship


  • Anti-Inflammatory Agents
  • Lipopolysaccharides
  • Nitric Oxide
  • Limonene
  • NOS2 protein, human
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse