Synthesis and Biological Evaluation of Oxindole Sulfonamide Derivatives as Bruton's Tyrosine Kinase Inhibitors

Bruton's tyrosine kinase (Btk) is a promising molecular target for several human B-cell-related autoimmune disorders, inflammation, and haematological malignancies. The pathogenic alterations in various Cancer tissues depend on mutant Btk for cell proliferation and survival, and Btk is also overexpressed in a range of hematopoietic cells. Due to this, Btk is emerging as a potential drug target to treat various human diseases, and several reversible and irreversible inhibitors have been developed and are being developed. As a result, Btk inhibition, clinically validated as an Anticancer treatment, is finding great interest in B-cell malignancies and solid tumours. This study focuses on the design and synthesis of new oxindole sulfonamide derivatives as promising inhibitors of Btk with negligible off-target effects. The most cytotoxic compounds with greater basicity were PID-4 (2.29±0.52 μM), PID-6 (9.37±2.47 μM), and PID-19 (2.64±0.88 μM). These compounds caused a selective inhibition of Burkitt's lymphoma RAMOS cells without significant cytotoxicity in non-BTK cancerous and non-cancerous cell lines. Further, PID-4 showed promising activity in inhibiting Btk and downstream signalling cascades. As a potent inhibitor of Burkitt's lymphoma cells, PID-4 is a promising lead for developing novel chemotherapeutics.

Antiproliferation; B-cell malignancies; Bruton's tyrosine kinase; Cytotoxicity; Knoevenagel condensation; Oxindole sulfonamide.