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Design, Synthesis, and Characterization of Novel Linomide Analogues and their Evaluation for Anticancer Activity
Rudrax N S Priolkar1, Sunil Shingade1, Mahesh Palkar2
1Department of Pharmaceutical Chemistry, PES's Rajaram and Tarabai Bandekar College of Pharmacy, Farmagudi, Goa 403401, India.
Background:
According to WHO, in 2017, about 90.5 million people suffered from cancer and about 8.8 million deaths occurred due to disease. Although the chemotherapeutic agents have decreased the mortality among the cancer patients but high toxicity and non-specific targets are still major drawbacks. Many researchers have identified linomide, a 4-hydroxy-2-quinolone derivative, as a lead molecule for the development of anticancer agents. With this background, we thought of the following objective.
Objective:
The objective of this research work involves the synthesis of a series of N-(2-(4- hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)-2-oxoethyl)-N-alkyl substituted benzene sulfonamides IVa-d (1-3) by replacing the anilide moiety at the third position of linomide with sulfamoylacyl and also N-methyl by N-phenyl functionality. To perform in silico anticancer activity by using Molegro Virtual Docker (MVD-2013, 6.0) software and in vitro anticancer activity by MTT assay.
Methods:
The starting material 4-hydroxy-1-phenylquinolin-2(1H)-one was treated with N-bromosuccinamide to yield compound II. Condensation of compound II with primary amines resulted in compounds IIIa-d, which, on coupling with substituted aromatic sulfonyl chlorides yield the title compounds IVa-d (1-3).
Results:
All the synthesized compounds were satisfactorily characterized by spectral data. The results of docking revealed that the synthesized compounds exhibited well-conserved hydrogen bonds with one or more amino acid residues in the active pocket of EGFRK tyrosine kinase domain (PDB ID: 1m17). The MolDock Score of compound IVd-1 (-115.503) was the highest amongst those tested. The in vitro anticancer activity results showed that compound IVc-1 (R= - (CH2) 2-CH3 ; R'= -H) and IV d-1 (R= -CH2-C6H5; R'= -H) were found to be most potent against K562 cell line with an IC50 of 0.451 μM/ml and 0.455 μM/ml respectively. Compound IVd-1 also showed better potency against A549 cell line with IC50 value of 0.704 μM/ml.
Conclusion:
The results of in silico and in vitro anticancer activity are in agreement with each other. Compound IV d-1 was found to be most active of the series.
Insights
Researchers synthesized novel anticancer agents based on the linomide structure. Compound IVd-1 demonstrated significant in vitro anticancer activity against K562 and A549 cell lines, showing promising potential for cancer treatment.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Computational Chemistry
Background:
- Cancer remains a leading cause of death globally, with chemotherapy's limitations including toxicity and non-specific targeting.
- Linomide, a 4-hydroxy-2-quinolone derivative, has emerged as a promising lead molecule for developing new anticancer agents.
- This study aimed to synthesize and evaluate novel linomide analogs with improved therapeutic potential.
Purpose of the Study:
- To synthesize a series of novel N-(2-(4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)-2-oxoethyl)-N-alkyl substituted benzene sulfonamides.
- To evaluate the in silico anticancer activity of the synthesized compounds using Molegro Virtual Docker.
- To determine the in vitro anticancer activity of the synthesized compounds using MTT assay.
Main Methods:
- Synthesis of title compounds IVa-d (1-3) through a multi-step process involving bromination, condensation with amines, and coupling with sulfonyl chlorides.
- In silico molecular docking studies against the EGFRK tyrosine kinase domain (PDB ID: 1m17).
- In vitro anticancer activity assessment using MTT assay on K562 and A549 cancer cell lines.
Main Results:
- All synthesized compounds were characterized by spectral data.
- Docking analysis revealed favorable interactions with the EGFRK active site, with compound IVd-1 achieving the highest MolDock Score (-115.503).
- Compounds IVc-1 and IVd-1 exhibited potent in vitro activity against K562 cells (IC50: 0.451 μM/ml and 0.455 μM/ml, respectively). Compound IVd-1 also showed significant activity against A549 cells (IC50: 0.704 μM/ml).
Conclusions:
- The in silico and in vitro results are consistent, supporting the compounds' anticancer potential.
- Compound IVd-1 emerged as the most active compound in the series, demonstrating significant efficacy against tested cancer cell lines.
- These findings highlight the potential of novel linomide derivatives as effective anticancer agents.
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