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

Bruton's 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.