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Design, Synthesis and Pharmacological Evaluation of Gastro-protective Anti-inflammatory Analgesic Agents based on Dual Oxidative Stress / Cyclooxygenase Inhibition.

Monika Gaba,Sarbjot Singh,C. Mohan,Richa Dhingra,M. Chauhan,P. Rana,Neelima Dhingra

Published 2020 in Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry

ABSTRACT

BACKGROUND Non-steroidal anti-inflammatory drugs (NSAIDs) derived local generation of reactive oxygen species (ROS) plays a crucial role in the formation of gastric ulceration. OBJECTIVE Therefore, anti-inflammatory analgesics with potent antioxidant activity could be a potential therapeutic strategy for treatment of pain and inflammatory disorders without gastrointestinal (GI) side effects. METHODS In an effort to develop gastro protective analgesic and anti-inflammatory agents, a series of 2-methylamino-substituted-1H-benzo[d] imidazol-1-yl) (phenyl) methanone derivatives was 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 action. 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 were performed. 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 anti-inflammatory 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 activity 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 activity could hold a great promise for further development of GI-safer NSAIDs.

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