Structural and functional insight into thiazolidinone derivatives as novel candidates for anticancer drug design: in vitro biological and in-silico strategies

Abstract

The compounds 2a–2h containing a thiazolidinone pharmacophore were synthesized via hetrerocylization of thiosemicarbazones with dimethyl acetylenedicarboxylate. The hybrid molecules were evaluated for anticancer activity against the human cell lines MCF-7, T47D (human breast adenocarcinoma) and HeLa (cervical cancer). Compounds 2c showed effective cytotoxicity on MCF-7 and HeLa (GI₅₀ 6.40 ± 0.10 μM/mL and GI₅₀10.30 ± 1.09 μM/mL), and compound 2d also showed effective cytotoxicity against MCF-7 and HeLa cell lines i.e., (GI₅₀ 16.60 ± 0.21 μM/mL and GI₅₀ 15.02 ± 0.14 μM/mL). These findings were comparable to cisplatin (azane;dichloroplatinum) the standard drug (GI₅₀ 13.20 ± μM/mL and 15.10 μM/mL respectively) and consequently nominated for determination of the mode of cell death. The results revealed the cytotoxic effects of 2c and 2d by induction of apoptosis in MCF-7 and HeLa cell lines. Moreover the results were further supported by the Molecular Docking which predicts the binding interactions of the best anticancer ligands with Ribonucleotide reductase (RNR), which is essential enzyme required for de-novo synthesis of DNA precursors. Molecular dynamic simulations were also performed to determine the stability of protein-ligand complex under different simulated conditions. In addition, the computational studies including DFTs, ADMET properties suggested these compounds can act as lead molecules, for the synthesis of novel drug candidates for the treatment of specific cancer and its associated malignancies.

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Keywords:

• Apoptosis
• cytotoxicity
• phosphatidylserine
• TUNEL
• molecular docking
• DFTs
• ADMET
• ribonucleotide reductase
• MD simulation

Acknowledgement

The author Syeda Abida Ejaz is grateful to the Offices of Research, Innovation and Commercialization (ORIC), The Islamia University of Bahawalpur, Pakistan for the financial support through Project No. 3890/ORIC/IUB/2021.

Disclosure statement

No potential conflict of interest was reported by the author(s).