Design, Synthesis, and Molecular Docking Studies of Coumarin-chalcone Conjugates as Selective TNF-α and Weak COX-2 Inhibitors with Efficacy as an Antioxidant.

INTRODUCTION Inflammation and oxidative stress play important roles in the development of various chronic diseases, necessitating compounds with dual therapeutic potential.

Methods

A series of (E)-7-hydroxy-4-methyl-6-(3-(substituted phenyl)acryloyl)-2H-chromen-2-one (7a-m) were synthesized starting from 7-hydroxy-4-methyl coumarin. The synthesized compounds were evaluated for their in vitro antioxidant and anti-inflammatory activity Results: Compound 7a exhibited the most potent antioxidant activity with an IC50 value of 83.39 μM. Compound 7b was found to be nearly 1.5-fold more potent in inhibiting albumin protein denaturation than ibuprofen and diclofenac at 100 μg/ml. Compound 7b displayed the most potent inhibitory activity against TNF-α and weak inhibition against the COX-2 enzyme with an IC50 value of 4.32 and 419.04 μM, compared to standard ibuprofen (IC50 value of 5.0 μM against COX-2) and diclofenac (IC50 value of 21.0 μM against TNF-α). Molecular docking studies of compound 7b showed the highest docking score against TNF-α and COX-2 enzymes, compared to the standard celecoxib.

Discussion

It was found that chloro at the 2nd position or methoxy at the 3rd position led to promising anti-inflammatory activity. Removal of the chloro group led to a decrease in COX-2 and TNF-α inhibitory activity. In the molecular docking studies, compound 7b shows a similar binding interaction against TNF-α and COX-2 as the standard celecoxib. The DFT studies showed favorable interactions, good stability, and moderate reactivity within the biological targets.

Conclusion

Based on the results of the present study, it is suggested that coumarin-chalcone derivatives may act as a lead for the synthesis of more potent antioxidants and anti-inflammatory compounds.