ORIGINAL RESEARCH Synthesis and biological evaluation of novel series of chalcone derivatives as inhibitors of cyclooxygenase and LPS-induced TNF-a with potent antioxidant properties Babasaheb P. Bandgar • Baliram S. Hote • Nagesh A. Dhole • Rajesh N. Gacche Received: 26 January 2011 / Accepted: 8 July 2011 / Published online: 28 July 2011 Ó Springer Science+Business Media, LLC 2011 Abstract Novel series of chalcones were synthesized and were evaluated as possible anti-inflammatory agents target- ing the cyclooxygenase-1 and 2 (COX-1 and 2), b-glucu- ronidase, trypsin, and TNF-a. Amongst the tested chalcones the compound 4k was found to be most effective inhibitor of TNF-a exhibiting 85% inhibition activity (IC 50 = 0.1 lM). The compounds 4a, 4f, 4l, and 4m were found to inhibit the COX-1 activity in as a range of 79.95–68.47% and COX-2 inhibition ranging 84.45–74.77%. The compounds 4l (81.71%) and 4f (72.10%) were found to be excellent inhibitors of trypsin and b-glucuronidase, respectively. Keywords WBCs  TNF-a  COX-1  COX-2  Antioxidant  Enzyme inhibition Introduction Chalcone is one of the major classes of natural product with wide spread distribution in fruit, vegetables, spices, tea, and soya-based foodstuff and it has been recently subjects of great interest for their interesting pharmaco- logical activities (Di Carlo et al., 1999). Chalcones, or 1,3- diaryl-2-propen-1-ones, belong to the flavonoid family. Chemically they consist of open chain flavonoids wherein the two aromatic rings are joined by a three-carbon a, b-unsaturated carbonyl system. Varieties of naturally occurring chalcones are polyhydroxylated in the aryl rings. The radical quenching properties of the phenolic groups present in many chalcones have raised interest in using the compounds or chalcones rich plant extract as drugs or food preservatives (Dhar, 1981). A vast body of literature has accumulated in the recent past linking the importance of chalcones as anti-inflammatory agents involved in inhibi- tion of cell migration and inhibition of TNF-a synthesis in mouse (Herencia et al., 2001). Many citations describe the diverse biological activities of chalcones and related derivatives as anti-cancer (Xia et al., 2000; Bois et al., 1998), anti-inflammatory (Hsieh et al., 1998, 2000; Her- encia et al.,1998), antimitotic (Ducki et al., 1998), antitu- bercular (Linn et al., 2002), cardiovascular (Furman et al., 2001), and hyperglycemic agents (Satyanarayana et al., 2004). Cyclooxygenase (COX) is the rate-limiting enzyme of the prostanoid biosynthetic pathway and it catalyzes the conversion of arachidonic acid to important inflammatory mediators such as prostaglandins (PGs), prostacyclins, and thromboxanes (Vane and Botting, 1996). The existence of enzyme cyclooxygenase in its two distinct isoforms and thus nonselective action of classical non-steroidal anti- inflammatory drugs (NSAIDs) results in certain mecha- nism-based side effects including dyspepsia, gastrointesti- nal ulcerations, bleeding, and nephrotoxicity (Pairet and Engelhardt, 1996). Both the isoforms differ in their regu- lation and expression. The constitutive COX-1 is respon- sible for the biosynthesis of PGs, which involves the cytoprotection of gastrointestinal tract and platelet aggre- gation (Kujubu et al., 1991). COX-2 is induced by pro- B. P. Bandgar (&) Medicinal Chemistry Research Laboratory, School of Chemical Sciences, Solapur University, Solapur, Maharashtra, India e-mail: bandgar_bp@yahoo.com B. P. Bandgar  B. S. Hote Organic Chemistry Research Laboratory, School of Chemical Sciences, SRTM University, Nanded, Maharashtra, India N. A. Dhole  R. N. Gacche Biochemistry Research Laboratory, School of Life Sciences, SRTM University, Nanded, Maharashtra, India 123 Med Chem Res (2012) 21:2292–2299 DOI 10.1007/s00044-011-9746-6 MEDICINAL CHEMISTR Y RESEARCH