Oxindole-based SYK and JAK3 dual inhibitors for rheumatoid arthritis: designing, synthesis and biological evaluation.

ABSTRACT

AIM: Autoimmune disorders have complex pathophysiology and focus is laid on the development of multitargeted agents. Two well-established kinases SYK and JAK3, were considered to design dual inhibitors as potential therapeutics using various molecular-modeling approaches. Mehodology Pharmacophore models for SYK and JAK3 were generated using oxindole-based inhibitors. Furthermore, an in-house database was designed that was screened against the best selected models. The obtained hits were employed for docking analysis and subjected to MM-GBSA analysis and molecular dynamic simulation. RESULTS: Top five oxindole derivatives were synthesized and evaluated for in vitro SYK and JAK3 activity. The most active compound 4a was evaluated for in vivo antiarthritic activity. It showed significant anti-arthritic activity. CONCLUSION: Thus, the designed inhibitors resulted in potential therapeutic agents for rheumatoid arthritis.