Nitrogen-containing Heterocyclic Derivatives of 1,3-Thiazolidine-2,4- Diones as Dual Anti-inflammatory and Anti-oxidant Agents and their Docking Studies

Abstract

Aim: The aim of this study was to carry out synthesis and characterization of nitrogencontaining heterocyclic derivatives of 1,3-thiazolidine-2,4-diones as dual anti-inflammatory and antioxidant agents and their docking studies. Background: Inflammation is a protective mechanism of our body to reduce injury and infection by microorganisms. The COX-2 enzyme is responsible for the production of prostaglandins (PG1), which are responsible for pain, fever, and a variety of other inflammatory symptoms. Reactive oxygen species (ROS) are important signalling molecules during inflammatory diseases. In an inflammatory state, polymorphonuclear neutrophils (PMNs) produce oxidative stress, which causes inter-endothelium junctions to open and the transfer of inflammatory cells over the endothelial barrier to increase. Tissue damage is caused by these inflammatory cells. Objective: The objective was to club thiazolidinediones with benzimidazole, triazole, and indole to achieve an enhanced anti-inflammatory effect. Method: In the current report, we have synthesized three new series of indole/ benzimidazole/benzotriazole clubbed with 5-arylidene-2,4-thiazolidinediones. The synthesized compounds were tested for in vivo anti-inflammatory activity using a carrageenan-induced rat paw edema model and in vitro antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing ability of plasma (FRAP) and hydrogen peroxide methods. Result: The results demonstrated that the compound PC-5 exhibited significant anti-inflammatory activity with 61.9% inhibition in comparison to the standard drug diclofenac sodium (71.4% inhibition) after 3h. The compound PC-5 exerted the highest antioxidant activity with an IC50 value of 24.68 μM amongst all synthesized compounds. Acute toxicity was also evaluated for all synthesized compounds, and the results indicated that all evaluated compounds were nontoxic in animals. The replacement of benzotriazole with benzimidazole and indole moieties diminished the anti-inflammatory activity. The hydroxysubstituted arylidene showed higher activity than methoxy, chloro substituted arylidene-2,4- thiazolididiones. Docking studies revealed that the compound PC-5 showed higher inhibition activity against the COX-2 receptor rather than COX-1. The ADME properties were also assessed that showed no violation of Lipinski’s rule and no toxicity. Conclusion: The substituents were found to exert varied activity. The docking studies revealed that the compounds showed lesser binding energy with COX-1 as compared to standard drug diclofenac. Moreover, the binding with COX-2 exhibited more binding energy, thereby proving to have specific COX2 inhibitory activity. All synthesised compounds have shown good antioxidant activity in addition to antiinflammatory activity. PC-5, PC-4, PB-5, PB-4, PA-5, and PA-4 were found to have increased antioxidant activity. Because of the presence of an electron-releasing hydroxyl group, PC-5 has proven to be a highly potent antioxidant agent.