R ESEARCH ARTICLE doi: 10.2306/scienceasia1513-1874.2021.076 Syntheses of phenylbutanoid and dienone derivatives and their anti-inflammatory activity Preeyarat Onkum a , Thitinun Karpkird a , Mesayamas Kongsema b , Weerasak Taengphan c , Theerachart Leepasert a,* a Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900 Thailand b Department of Zoology, Faculty of Science, Kasetsart University, Bangkok 10900 Thailand c Expert Centre of Innovative Herbal Products, Thailand Institute of Scientific and Technological Research, Pathum Thani 12120 Thailand * Corresponding author, e-mail: fscitcl@ku.ac.th Received 9 Mar 2021 Accepted 14 Jun 2021 ABSTRACT: A series of phenylbutanoid 4a–e and dienone 5a–e derivatives were synthesized and characterized by spectroscopic methods. Cytotoxic and anti-inflammatory activities of the synthesized derivatives were investigated at a potentially non-toxic concentration of 15.63 μM (as indicated by cell viability of more than 70%) by measuring the nitric oxide content produced by lipopolysaccharide-stimulated RAW264.7 macrophage cells. Compounds 4b, 4e, 5a, 5b, and 5e at 15.63 μM showed a higher anti-inflammatory activity than the diclofenac drug without affecting cell viability of RAW264.7 macrophage cells. In particular, 5a and 5e showed a nitric oxide inhibition of more than 80%. KEYWORDS: nitric oxide inhibition, anti-inflammation, phenylbutanoid, dienone INTRODUCTION Nonsteroidal anti-inflammatory drugs (NSAIDs) are used for treatment of chronic inflammation and to relieve mild to moderate inflammatory symptoms. Examples of NSAIDs are: naproxen, ibuprofen, as- pirin, and diclofenac. However, NSAIDs are as- sociated with a risk of many adverse effects [1], the most important of which are gastrointestinal, cardiovascular, and liver adverse effects. In addi- tion, NSAIDs are associated with an increased risk for chronic kidney disease (CKD). A long-term use of diclofenac and aceclofenac was also reported to increase the risk of stroke by 64% after two years [2, 3]. Therefore, NSAIDs should be prescribed and used with caution to avoid adverse effects. Alter- native treatments using herbs and herbal products, such as ginger, turmeric, cannabis, cassumunar gin- ger, etc., are available to help relieve symptoms. Zingiber cassumunar Roxb., also known as Plai, is a medicinal plant normally found in Thailand. Its chemical constituents and biological activities have been studied, and the essential oil extracted from the plant’s rhizome has proven to be useful for health. The main components identified in Plai are α-terpinene, γ-terpinene, terpinen-4-ol, sabinene, and ( E)-4- (3,4-dimethoxyphenyl)butadiene (DMPBD) [4, 5]. It was reported that phenylbutanoids in the rhizome can reduce inflammation, and DMPBD showed inhibition in TPA (12-O-tetradecanoylphorbol- 13-acetate)-induced edema 11 times higher than diclofenac [6]. Furthermore, the enriched phenylbutanoids from Z. cassumunar extracts showed stronger anti-inflammatory activity than each individual phenylbutanoids. The dienone derivatives are analogs of cur- cumin. The curcumin was first isolated from turmeric and exhibited various biological activities. Thus, several curcumin analogs were synthesized. The biological activities of curcuminoids and syn- thetic curcumin analogs were studied, and the re- sults indicateed anticancer and antioxidant activi- ties with low toxicity to cells [7–9]. RAW264.7 macrophage cells play a role in the immune system as the first defence mechanism against invasion of unusual materials and inflamma- tion [10, 11]. Macrophages could be activated in the inflammatory process by lipopolysaccharide (LPS). Activated macrophages release several different chemical mediators including nitric oxide (NO), an important inflammatory mediator [12, 13]. Thus, NO production is important in the study of anti- inflammation activity, via the Griess reagent assay using nitrite content accumulated in the culture medium as an indicator of NO production [14]. www.scienceasia.org