Background: Non-steroidal anti-inflammatory drugs (NSAIDs) derived local
generation of reactive oxygen species (ROS) plays a crucial role in the formation of gastric
Objective: Therefore, anti-inflammatory analgesics with potent antioxidant activity could
be a potential therapeutic strategy for the treatment of pain and inflammatory disorders
without gastrointestinal (GI) side effects.
Methods: In an effort to develop gastroprotective analgesic and anti-inflammatory agents,
a series of 2-methylamino-substituted-1H-benzo[d] imidazol-1-yl) (phenyl) methanone derivatives
were synthesized and evaluated in vitro for cyclooxygenase (COX) inhibition as
well as anti-oxidant potential by the FRAP assay. The compounds with significant in vitro
COX-1/COX-2 inhibitory activity and antioxidant activity were further screened in vivo for
their anti-inflammatory and analgesic activities. Moreover, the ulcerogenic potential of test
compounds was also studied. To gain insight into the plausible mode of interaction of
compounds within the active sites of COX-1 and COX-2, molecular docking simulations
Results: Among the various synthesized molecules, most of the compounds showed good
cyclooxygenase inhibitory activity and efficient antioxidant activity in FRAP assay. After
preliminary and indicative in vitro assays, three compounds exhibited most significant antiinflammatory
and analgesic activity with better gastric tolerability during their in vivo
evaluation. Ligand interaction studies indicated highest dock score -43.05 of 1,2-
disubstituted benzimidazole derivatives in comparison to the reference ligand -30.70.
Overall studies provided us (2-((4-methoxyphenylamino) methyl) -1h-benzo [d] imidazol-
1-yl) (phenyl) methanone as a lead with potent gastro-protective anti-inflammatory and analgesic
activities that can be used for future research.
Conclusion: From the above results, it can be concluded that designing of multifunctional
molecules with COX-1/COX-2 inhibitory and anti-oxidant activities could hold a great
promise for further development of GI-safer NSAIDs.