Sadia AZEEM, Nasiara KARIM, Sadaf WADOOD, Nisar Zamin SHAH, Muhammad KIFAYATULLAH, Sudhair ABBAS, Ajmal KHAN, Peer Abdul HANNAN, Nazarul ISLAM
Journal of Research in Pharmacy - 2026;30(3):945-956
Enzymes involved in conversion of arachidonic acid into prostaglandins include Lipoxygenase and Cyclooxygenase, which play a crucial role in pro-inflammatory processes. Medicine that inhibit cyclooxygenase are classified as Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), which exhibit significant anti-inflammatory properties, along with several adverse effects, particularly on the gastrointestinal mucosa, attributed to presence of various functional groups. Hence, present research work is designed to develop safer anti-inflammatory derivatives of naproxen that possess dual inhibition capabilities for both Cyclooxygenase and Lipoxygenase pathways, while also has safety profile. Four derivatives of Naproxen (NS9-NS12) were synthesized through a three-step process and were characterized by 1H NMR, 13C NMR, HR-ESI-MS techniques. Additionally, the safety profile was checked according to OECD guidelines 423 where a single dose of 2000 mg/kg (b.wt) of all derivatives was administered through oral route.The in vitro anti-inflammatory activity was assessed through the Lipoxygenase and Cyclooxygenase inhibitory pathways. Derivatives were found safe up to dose 2000 mg/kg (b.wt) having no mortality and behavioral changes in any animals derivatives treated group. In Cyclooxygenase pathway, NS12 and NS11 demonstrated high significant inhibitory effect against cyclooxygenase 2, with IC50 value of 1.0 muM at concentration 1000-31.25 µg/mL in contrast to COX-1 indicates as potent COX-2 inhibitor. While the IC50 for NS9 and NS10 was 74.0 and 24.0 muM respectively on the same concentration. The IC50 for Celecoxib was 0.24 muM at concentration 1000-31.25 µg/ml. In Lipoxygenase pathway, NS11 exhibited an IC50 of <01 muM, also within the concentration range of 1000-31.25 µg/mL, with percent inhibition values of 91.23+/- 0.48, 87.44+/- 0.80, 85.72+/- 0.61, 81.65+/- 0.72, 77.86+/- 0.38, 73.45+/- 0.77. In comparison with Cyclooxygenase and Lipoxygenase activities, NS12 showed greater percent inhibition for Cyclooxygenase while for Lipoxygenase was NS11. From the docking conformation compound NS11 was found good docking score of -15.9737 formed four polar interactions, one pi-cation and five pi-H linkages with the active residues of the lipoxygenase enzyme.
