Synthesis and Biological Evaluation of Oxindole Sulfonamide Derivatives as Bruton\u27s Tyrosine Kinase Inhibitors

Bruton\u27s 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\u27s 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\u27s lymphoma cells, PID-4 is a promising lead for developing novel chemotherapeutics

Novel 5-Substituted Oxindoles Derivatives as Bruton\u27s Tyrosine Kinase Inhibitors: Design, Synthesis, Docking, Molecular Dynamic Simulation, and Biological Evaluation

Bruton\u27s tyrosine kinase (BTK) is a non-RTK cytoplasmic kinase predominantly expressed by haemopoietic lineages, particularly B-cells. A new Oxindole-based focused library was designed to identify potent compounds targeting the BTK protein as anticancer agents. This study used rational approaches like structure-based pharmacophore modelling, docking, and ADME properties to select compounds. The Molecular dynamics simulation analysis carried out at 20 ns supported the stability of compound 9g within the binding pocket. All the compounds were synthesized and subjected to biological screening on two BTK-expressing cancer cell lines, RAMOS and K562, and six non-BTK cancer cell lines, A549, HCT116 (parental and p53-/-), U2OS, JURKAT, and CCRF-CEM, and two non-malignant cell lines, BJ and MRC-5. This study resulted in the identification of four new compounds, 9b, 9f, 9g, and 9h, which displayed potent activity against BTK-high RAMOS cells. These four compounds, each possessing free binding energies of -10.8, -11.1, -11.3, and -10.8 Kcal/mol, demonstrated antiproliferative and cytotoxic effects in RAMOS cells with IC50 values falling within the lower sub-micromolar range

Novel 5‑Substituted Oxindole Derivatives as Bruton’s Tyrosine Kinase Inhibitors: Design, Synthesis, Docking, Molecular Dynamics Simulation, and Biological Evaluation

Bruton’s tyrosine kinase (BTK) is a non-RTK cytoplasmic kinase predominantly expressed by hemopoietic lineages, particularly B-cells. A new oxindole-based focused library was designed to identify potent compounds targeting the BTK protein as anticancer agents. This study used rational approaches like structure-based pharmacophore modeling, docking, and ADME properties to select compounds. Molecular dynamics simulations carried out at 20 ns supported the stability of compound 9g within the binding pocket. All the compounds were synthesized and subjected to biological screening on two BTK-expressing cancer cell lines, RAMOS and K562; six non-BTK cancer cell lines, A549, HCT116 (parental and p53–/–), U2OS, JURKAT, and CCRF-CEM; and two non-malignant fibroblast lines, BJ and MRC-5. This study resulted in the identification of four new compounds, 9b, 9f, 9g, and 9h, possessing free binding energies of −10.8, −11.1, −11.3, and −10.8 kcal/mol, respectively, and displaying selective cytotoxicity against BTK-high RAMOS cells. Further analysis demonstrated the antiproliferative activity of 9h in RAMOS cells through selective inhibition of pBTK (Tyr223) without affecting Lyn and Syk, upstream proteins in the BCR signaling pathway. In conclusion, we identified a promising oxindole derivative (9h) that shows specificity in modulating BTK signaling pathways