Phosphorylated Analogs of Paracetamol and Their Anti-Inflammatory Potential

Paracetamol is a widely used analgesic and antipyretic agent; however, its use is limited by minimal anti-inflammatory activity and the risk of hepatotoxicity from prolonged oral use or in acute overdose. To address these limitations, four novel phosphorylated paracetamol analogs (2a-2d) were synthesized via a UV-radical methodology and evaluated through integrated in silico, in vitro, and in vivo for anti-inflammatory dermal approaches. Molecular docking suggested plausible binding interactions with COX-1 and COX-2 for all analogs. In vitro cytotoxicity assays in THP-1 cells showed that 2a and 2b did not affect cell viability at 100 μM over 24 h. In a TPA-induced acute ear edema model in CD1 male mice, 2a produced about 50% inhibition of edema at the lowest tested quantity (0.5 mg/ear), representing a fourfold potency advantage over indomethacin at the same amount, while 2b displayed significant anti-inflammatory and vasoregulatory activity at higher quantities. Computational ADME profiling indicated that all analogs satisfy Lipinski's drug-likeness criteria and exhibit low predicted hERG channel risk. These results support N-phosphorylation of 4-aminophenol as a viable strategy to improve the topical anti-inflammatory efficacy of paracetamol analogs.