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Discovery of Substituted 2-oxoquinolinylthiazolidin-4-one Analogues as Potential EGFRK Inhibitors in Lung Cancer
Soniya Naik1,2, Vasu Soumya1, Shivlingrao N Mamledesai2
1Department of Pharmaceutical Chemistry, Sri Ramachandra Faculty of Pharmacy, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India.
Purpose:
Cancer is the second leading cause of death globally and is responsible for an estimated 9.6 million deaths in 2018. Globally, about 1 in 6 deaths is due to cancer and the chemotherapeutic drugs available have high toxicity and have reported side effects hence, there is a need for the synthesis of novel drugs in the treatment of cancer.
Methods:
The current research work dealt with the synthesis of a series of 3-(3-acetyl-2-oxoquinolin-1-(2H)-yl-2-(substitutedphenyl)thiazolidin-4-one (Va-j) derivatives and evaluation of their in-vitro anticancer activity. All the synthesized compounds were satisfactorily characterized by IR and NMR data. Compounds were further evaluated for their in-vitro anticancer activity against A-549 (lung cancer) cell lines. The in-vitro anticancer activity was based upon the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay method.
Results:
The synthesized compounds exhibited satisfactory anticancer properties against the A-549 cell line. The compound (VH): showed the highest potency amongst the tested derivatives against the A-549 cell line with IC50 values of 100 µg/ml respectively and was also found to be more potent than Imatinib (150 µg/ml) which was used as a standard drug. Molecular docking studies of the titled compounds (Va-j) were carried out using AutoDock Vina/PyRx software. The synthesized compounds exhibited well-conserved hydrogen bonds with one or more amino acid residues in the active pocket of the EGFRK tyrosine kinase domain (PDB 1m17).
Conclusion:
Among all the synthesized analogues, the binding affinity of the compound (Vh) was found to be higher than other synthesized derivatives and a molecular dynamics simulation study explored the stability of the docked complex system.
Insights
Novel anticancer drug candidates were synthesized and tested against lung cancer cell lines. Compound (Vh) demonstrated superior efficacy compared to Imatinib, with promising molecular docking results.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Oncology
Background:
- Cancer is a leading global cause of death, necessitating new treatments.
- Existing chemotherapeutics have significant toxicity and side effects.
- Novel drug development is crucial for effective cancer therapy.
Purpose of the Study:
- To synthesize novel quinolinyl-thiazolidinone derivatives.
- To evaluate the in vitro anticancer activity of these compounds.
- To identify potent anticancer agents with improved safety profiles.
Main Methods:
- Synthesis of 3-(3-acetyl-2-oxoquinolin-1-(2H)-yl-2-(substitutedphenyl)thiazolidin-4-one derivatives (Va-j).
- Characterization using IR and NMR spectroscopy.
- In vitro anticancer activity assessment against A-549 lung cancer cell lines using the MTT assay.
- Molecular docking studies against EGFRK tyrosine kinase domain (PDB 1m17).
Main Results:
- Synthesized compounds displayed significant in vitro anticancer properties.
- Compound (Vh) exhibited the highest potency against A-549 cells (IC50 = 100 µg/ml), outperforming the standard drug Imatinib (150 µg/ml).
- Molecular docking revealed favorable interactions and hydrogen bonding within the EGFRK active site.
Conclusions:
- Compound (Vh) demonstrated superior binding affinity and anticancer potency among the synthesized derivatives.
- Molecular dynamics simulations confirmed the stability of the docked complex.
- These findings highlight the potential of quinolinyl-thiazolidinone derivatives as novel anticancer agents.
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