Synthesis, in silico ADMET, and molecular docking studies of novel 3-substituted- 5-[(4-oxo-4<i>H</i>-chromen-3-yl)methylene]−2-(2-phenylhydrazineylidene)thiazolidin-4-ones inducing apoptosis, autophagy, and cell cycle arrest in breast cancer cell li

A novel class of 3-Substituted-5-[(4-oxo-4<i>H</i>-chromen-3-yl)methylene]−2-(2-phenylhydrazineylidene)thiazolidin-4-one (3a-g and 5) was efficiently synthesized via a one-pot three components involving 1-phenyl-4-substituted-thiosemicarbazide, ethyl bromoacetate and 3-formylchromone in absolute ethanol and freshly fused sodium acetate under the effect of ultrasound irradiation at 50 °C. The target compounds were obtained in excellent yields within a short time. The synthesized compounds were evaluated for their cytotoxic potential against human breast cancer cell lines MCF-7 and MDA-MB-231 using the sulforhodamine B (SRB) assay. Both compounds 3a and 3f exhibited markedly enhanced cytotoxic activity in comparison to the reference drugs doxorubicin and tamoxifen. These bioactive molecules significantly promoted late-stage apoptosis and necrosis across all tested tumor cell lines. Furthermore, compounds 3a and 3f demonstrated a strong capacity to cause cell-cycle arrest at the G1 and S phases. Additionally, compounds 3a and 3f had potential autophagic induction. ADMET analysis revealed that compound 3a displayed superior oral absorption, a more favorable pharmacokinetic profile, lower toxicity, and no mutagenic risk. Molecular docking studies indicated that both 3a and 3f interact effectively with the VEGFR-2 receptor. These findings suggested that these compounds possess a valuable skeletal structure for the development of novel antitumor agents.