Exploring the Potential of Substituted 4-Thiazolidinone Derivatives in the Treatment of Breast Cancer: Synthesis, Biological Screening and In Silico Studies

Abstract

A series of 4-thiazolidinone conjugates bearing quinoline/indole/furan scaffolds were designed as potential anti-breast cancer agents, synthesized, and investigated for their anti-breast cancer, and anti-oxidant activity. The anticancer activity was performed using MTT assay against breast cancer cell lines such as MCF-7 and MDA-MB-231 and the results demonstrated that most of the compounds were sensitive to cancer cell lines. Compounds GT1, GT2 and GT5 showed remarkable potency against MCF-7 cell lines with IC50 values of 11.64 µM, 11.27 µM and 11.37 µM respectively in comparison to standard drug doxorubicin with IC50 value of 11.80 µM. Compounds GT2 and GT5 exerted higher cytotoxic activity against the MDA-MD-231 cell line with IC50 value of 17.60 µM and 15.09 µM respectively than doxorubicin (IC50: 18.35 µM). The anti-oxidant activity was also performed by DPPH and hydrogen peroxide scavenging assay. Compounds GT2 and GT7 showed higher free radical scavenging activity with IC50 value of 11.39 µM and 11.28 µM respectively against DPPH assay and 10.99 µM and 11.20 µM respectively against hydrogen peroxide assay. The molecular docking study was carried out against estrogen receptor alpha (PDB ID: 4IVY) to identify the mechanism of action of synthesized compounds using molecular docking and molecular dynamics simulation. The results showed that compounds GT1, GT2, and GT5 showed higher docking score −110.922 kcal/mol, −124.618 kcal/mol and-116.029 kcal/mol respectively as compared to reference (doxorubicin) drug (-109.847 kcal/mol). The ADME and toxicity profile was predicated by Schrodinger QikProp program. All the synthesized compounds showed no violation of Lipinski’s rule except GT2. The molecule insight behavior was predicted by using MD simulation. According to in silico and in vitro studies GT1, GT2, and GT5 showed anti-cancerous activity against MCF-7.