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Diaryl Ether Derivatives as Dual Inhibitors of Selective COX-2 and EGFR: Synthesis, In silico, and In Vitro Analysis
Vivekananda Saha1, Aynal Hoque1, Abbas Ali1
1Department of Chemistry, Cooch Behar Panchanan Barma University, Panchanan Nagar, Cooch Behar, 736101, WB, India.
Introduction:
The rising prevalence of cancers with chronic inflammation is a leading global health concern. Modern anticancer treatments require dual inhibitors of cyclooxygenase- 2 (COX-2) and Epidermal Growth Factor Receptor (EGFR) with minimal adverse effects.
Methods:
The emergence of diaryl ether derivatives has encouraged the development of new therapeutic strategies for inflammation-linked conditions. A series of nine diaryl ether derivatives was designed, and in silico studies were performed to predict their interactions with COX- 1, COX-2, and EGFR proteins. Drug likeness and toxicity characteristics were investigated using Swiss ADME, ADMET Lab 2.0, and ProTox-3.0 tools. Furthermore, to observe the selective COX-2 inhibitory nature, a protein (bovine serum albumin (BSA)) denaturation study of the five best compounds with high binding affinities was conducted.
Results:
Nine diaryl ether derivatives were synthesized and characterized using 1H-NMR, 13C NMR, LC-MS, and FT-IR spectroscopy. Based on the docking score and pharmacokinetics, compound 12a showed a significant IC50 value of 39.24 μg/mL in the BSA denaturation assay. To screen the kinetic behavior of five selected compounds with high binding affinities (11a, 12a, 12b, 12c, and 13a) with COX-2, Molecular Dynamics (MD) simulations were performed for 100 ns. MD simulations and binding free energy calculations were performed to observe the stability of the best-docked EGFR-12a complex with a docking score of -9.5 kcal/mol.
Conclusion:
This study focused on the synthesis and biological analysis with theoretical explanations. Overall, diaryl ether derivatives are promising precursors for anti-inflammatory and anticancer drugs in the biomedical field.
Insights
New diaryl ether derivatives show promise as dual inhibitors for treating inflammation-linked cancers. Compound 12a demonstrated significant potential in preclinical evaluations for anticancer and anti-inflammatory drug development.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Pharmacology
Background:
- Rising global cancer incidence linked to chronic inflammation necessitates novel therapeutic agents.
- Current treatments often target cyclooxygenase-2 (COX-2) and Epidermal Growth Factor Receptor (EGFR), but require improved safety profiles.
Purpose of the Study:
- To design, synthesize, and evaluate novel diaryl ether derivatives as potential dual COX-2 and EGFR inhibitors.
- To investigate the in silico and in vitro anti-inflammatory and anticancer properties of these compounds.
Main Methods:
- Synthesis and characterization of nine diaryl ether derivatives.
- In silico analysis including molecular docking, drug likeness, and toxicity prediction.
- In vitro evaluation using bovine serum albumin (BSA) denaturation assay and molecular dynamics simulations.
Main Results:
- Compound 12a exhibited a significant IC50 value of 39.24 μg/mL in the BSA denaturation assay.
- Molecular docking revealed a strong binding affinity for compound 12a with EGFR (-9.5 kcal/mol).
- Molecular dynamics simulations confirmed the stability of the EGFR-12a complex.
Conclusions:
- Diaryl ether derivatives represent a promising scaffold for developing novel anti-inflammatory and anticancer therapeutics.
- Compound 12a shows significant potential for further investigation in preclinical and clinical studies.
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