Moderate COX-2 inhibitors with favorable safety profiles might benefit the treatment of ulcerative colitis. Herein, biochemical differences between COX-1 and COX-2 enzymes were exploited to identify a strategy for converting the nonsteroidal anti-inflammatory drug indoprofen into moderately selective COX-2 inhibitors through the installation of amides (7a-7y) and sulfonamides (8a-8g) at its C-7 position. The cyclooxygenase inhibition assays dementated that compounds 7m, 7x, 7y, and 8d, displayed moderate selectivity towards the COX-2 enzyme (selectivity indexes = 10.57-18.35) compared with indoprofen (selectivity index = 0.78) and celecoxib (selectivity index = 57.47). 7y was also more effective in anti-inflammatory than celecoxib, observed by inhibiting NO, TNF-alpha, and IL-6 towards lipopolysaccharide-induced murine macrophages. An absorption, distribution, metabolism, and excretion study revealed that the compounds were promising new oral anti-ulcerative colitis agents. More importantly, 7y exhibited better gastric safety profiles than indoprofen in vivo. 7y also strongly protects against DSS-induced ulcerative colitis, evidenced by significantly mitigating histological damage. The study suggested that the structural modification at the C-7 position of indoprofen can reduce its COX-1 inhibition while converting it into a moderately selective COX-2 inhibitor; compound 7y represents a promising lead for treating ulcerative colitis with minimal gastrointestinal side effects.