Novel series of chalcones were synthesized and were evaluated as possible anti-inflammatory agents targeting the cyclooxygenase-1 and 2 (COX-1 and 2), b-glucuronidase, 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 (IC50 = 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.