Work

Design, synthesis, and biological evaluation of novel oxindole-based derivatives as potent and selective antileukemic agents.

Year: 2026

Type: article

Abstract: Acute lymphoblastic leukemia (ALL) is an aggressive hematological malignancy that requires rapid therapeutic intervention. In this study, a series of oxindole-based derivatives ( 5a-t ) was designed, synthesized, and evaluated for antiproliferative activity. Initial single-dose screening at the NCI-DTP identified five compounds for full five-dose evaluation. Among these, compound 5t emerged as the most potent analogue, demonstrating broad antiproliferative activity across the NCI-60 panel with GI 50 (MG-MID) values ranging from 9.05–45.24 μM and exhibiting pronounced selectivity toward leukemia cell lines. Compound 5t showed superior cytotoxicity against CCRF-CEM cells while displaying markedly lower toxicity toward normal fibroblasts (BJ and MRC-5), yielding selectivity indices >17, thereby outperforming ibrutinib. Kinase profiling revealed that 5t functions as a multi-kinase inhibitor, potently targeting JAK3, VEGFR2, and FGFR1, with sustained inhibition observed at low micromolar concentrations. Mechanistic studies further demonstrated dose-dependent S-phase accumulation, accompanied by a slight increase in the G2/M DNA-content fraction in CCRF-CEM cells, accompanied by a near-complete shutdown of bulk RNA and DNA synthesis by the most potent analogue 5o . Complementary molecular modeling supported stable binding of 5t to JAK3 and VEGFR2, while in silico ADME predictions indicated favorable oral drug-like properties. Collectively, these findings identify as a viable candidate for further preclinical evaluation for the development of new therapeutic agents against ALL.

Source: European Journal of Medicinal Chemistry Reports

DOI: 10.1016/j.ejmcr.2026.100376