Design and Optimization of Spiro-Isatin-Thiazolidinone Hybrids with Promising Anticancer Activity

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Pharmacology

Background:

• Cancer remains a significant global health challenge with limitations in current treatments.
• Targeting the MDM2-p53 interaction is a key anticancer strategy due to pathway dysregulation in tumors.
• Spiro-isatin-thiazolidinone derivatives show potential but need optimization for potency and selectivity.

Purpose of the Study:

• To design, synthesize, and evaluate novel spiro-isatin-thiazolidinone hybrids.
• To enhance cytotoxicity against cancer cells while reducing toxicity to normal cells.
• To investigate the potential of these hybrids as anticancer agents targeting the MDM2-p53 pathway.

Main Methods:

• Molecular docking against MDM2 for derivative design and optimization.
• In vitro cytotoxic evaluation using MTT assays on various cancer and normal cell lines.
• Molecular dynamics simulations for binding stability assessment and in silico ADMET property prediction.

Main Results:

• Several derivatives displayed micromolar cytotoxicity.
• Compound 18 exhibited potent and selective anticancer activity (IC50 6.67-8.37 µM in cancer cells, >100 µM in HaCaT cells).
• Compound 18 showed strong MDM2 binding affinity, stable interactions, good oral bioavailability, and compliance with Lipinski's Rule of Five.

Conclusions:

• Novel spiro-isatin-thiazolidinone hybrids, especially compound 18, possess potent and selective anticancer properties.
• Compound 18 demonstrates favorable pharmacokinetic and toxicity profiles, indicating its therapeutic potential.
• These findings support the development of spiro-isatin-thiazolidinone derivatives as targeted anticancer agents.