Discovery of new indole-thiazolidin-4-one hybrid derivatives as anticancer agents: Synthesis, biological evaluation, molecular docking toward VEGFR-2 , and DFT studies.

A new series of indole–thiazolidin-4-one hybrid derivatives ( IN-1–IN-5 ) was designed and synthesized as potential anticancer agents by integrating two biologically privileged scaffolds into a single molecular framework. The compounds were characterized using standard spectroscopic techniques and evaluated for their in vitro anticancer activity against human breast cancer cell lines (MCF-7 and MDA-MB-231) and WI-38 normal human lung cells using the Microculture Tetrazolium (MTT) assay, with doxorubicin (DXN) as the reference drug. All compounds exhibited concentration-dependent cytotoxic effects, with IC₅₀ values ranging from 20.54 ± 2.57 to 152.46 ± 3.43 µM for MCF-7 cells and from 13.30 ± 0.51 to 95.48 ± 2.83 µM for MDA-MB-231 cells. Among them, IN-5 was the most potent, showing IC₅₀ values of 20.54 ± 2.57 µM (MCF-7) and 13.30 ± 0.51 µM (MDA-MB-231), approaching the activity of doxorubicin. Structure–activity relationship analysis revealed that substituents on the imine nitrogen of the thiazolidinone ring significantly influence activity, with polar and hydrogen-bonding groups enhancing potency. Molecular docking studies against VEGFR-2 kinase demonstrated that IN-5 exhibited a favorable binding affinity (-8.62 kcal/mol), comparable to sunitinib (-8.36 kcal/mol), along with key interactions within the active site. Furthermore, density functional theory (DFT) calculations provided insight into the electronic properties and reactivity of the compounds. These findings identify IN-5 as a promising lead compound and highlight indole-thiazolidin-4-one hybrids as a valuable scaffold for the development of novel anticancer agents with potential VEGFR-2 inhibitory activity.