Design And Synthesis Of Sulfonamides Containing New Pteridine Analogues For The Management Of Rheumatoid Arthritis

Objective: This study involved the Design and synthesis of novel pteridine derivatives linked to sulfonamide molecules (5a-f) and their study of antioxidant, antiarthritic activity, and molecular docking capability towards the rheumatoid arthritis (RA) associated targets. Materials and Methods: The synthesis of the target compounds involved a multiple-step synthetic procedure and was characterized by FT-IR, 1D NMR (1H NMR and 13C NMR), and mass spectroscopy. Antioxidant activity was measured using the DPPH free radical scavenging assay, and antiarthritic activity was determined by the Complete Freund’s Adjuvant (CFA) induced arthritis in Wistar rats by assessing oedema of the paws for 28 days. Molegro Virtual Docker was used to perform molecular docking studies against the human dihydroorotate dehydrogenase complexed with antiproliferative agent (PDB: 1D3H) to assess molecular interaction patterns and binding affinity. Results and Discussion: The synthesized derivatives were found to yield good yields (82-86%) and maintained the structural integrity of the derivatives when analyzed by spectral characterization. However, compound 5b had the most potent antioxidant activity among all the compounds, with an IC50 value of 28.77 ± 0.86 µg/mL, which was higher than that of ascorbic acid. In the evaluation of antiarthritic activity, compound 5b exhibited a strong antiarthritic activity response with a maximum paw oedema inhibition of −43.68% on day 28. Its activity was also corroborated using molecular docking analysis, where compound 5b possessed the highest binding affinity (MolDock score: -193.269 kcal/mol) with favorable hydrogen bonding interactions with critical amino acids such as Thr212, Asn382, and His388. Conclusion: These findings indicate that compound 5b, with high antioxidant and antiarthritic efficacy and significant molecular interactions, could be a potential lead compound for developing novel drug molecules for RA.