Development of Novel Nimesulide Analogues as Potential Candidates for Pancreatic Ductal Adenocarcinoma

Pancreatic Ductal Adenocarcinoma (PDAC) is a highly aggressive malignancy with the lowest survival rates worldwide. Recent studies have demonstrated that reactive oxygen species (ROS) play a significant role in PDAC progression through the remodeling of the tumor microenvironment, promotion of metastasis, and activation of inflammatory signaling pathways. Although non-steroidal anti-inflammatory drugs (NSAIDs) are known to regulate these processes, their effects on pancreatic cancer remain unclear. This study aimed to develop novel Nimesulide derivatives with enhanced antioxidant potential. In this context, a series of compounds (2a–j and 3a–c) were synthesized via chemical modification of Nimesulide, and their structural characterization was confirmed by FTIR, 1H-NMR, 13C-NMR, and MS analyses. The synthesized compounds were evaluated using a DPPH radical scavenging assay to ascertain their antioxidant activities, and some derivatives exhibited notable activity. Furthermore, the interactions of the compounds with COX-2 and MetAP2 enzymes were investigated using molecular docking. The results indicated that some compounds interacted with COX-2 at alternative hydrophobic pockets rather than the active site, whereas they exhibited strong binding affinity toward MetAP2 by forming multiple interactions with active site amino acid residues. These findings suggest that the synthesized Nimesulide derivatives represent promising antioxidant compounds with favorable in silico interactions toward PDAC-associated targets, warranting further biological evaluation for potential therapeutic applications.