Background Rheumatoid arthritis (RA) is a chronic inflammatory disease which is easily recognised by unrelenting inflammation, joint erosion, joint immobility and severe debilitation. The cause of the disease suggests that, T cells, B cells, macrophages, and dendritic cells gain access to the inflamed synovium causing progression of disease via generation of cytokines and autoantibodies. The current available therapies to treat RA target the immune response which in turn adversely affects the immunity of the patients.
Objectives The presents study deals with the discovery of 1,3,5-triazine-thiazoles targeting immune and non-immuno synovitis by via dual inhibition of NF-κB and EGFR-TKs for possible benefit in rheumatoid arthritis.
Methods The 1,3,5-triazine-thiazole hybrid derivatives were synthesized via cascade of nucleophillic and cyclo-condensation reaction. These inhibitors was screened for NF-kB transcriptional activity in RAW264.7 macrophages, whereas, EGFR-TKs inhibitor activity was assessed via kinase inhibition assay kit. The docking study was carried out with 3D-crystal structure of NF-κB and EGFR-TK to explicate the inhibitory action.
Results The designed hybrid analogues showed excellent inhibitory activity against both NF-κB and EGFR-TK. Particularly, against NF-κB, methyl (5c) containing molecule showed most significant activity (respectively with relative NF-κB activity: 1.82±1.87). Docking study suggests that, 5c was deeply buried in the DNA binding domain of NF-κB interacting with Tyr57, Val58, Cys59, His141, and Val142. In EGFR-TK inhibitory assay, the synthesized molecules showed IC50 ranging from 4.23–39.32μ M via interacting with Leu788, Met766, Lys745, Glu762 with 3D crystal structure of EGFR-TK.
Conclusions These results demonstrate the feasibility of 1,3,5-triazine-thiazole as dual inhibitior of NF-κB and EGFR-TKs for the treatment of inflammatory disorders such as rheumatoid arthritis in more efficient way.
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Acknowledgements Authors are thankfull to SHUATS for providing necessary infrastructural facilities.
Disclosure of Interest None declared
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