Targeting EGFR Tyrosine Kinase: Design, Synthesis and Biological Evaluation of Novel Quinazolinone Derivatives

Nematpour, Manijeh; Rezaee, Elham; Nazari, Maryam; Hosseini, Omid; Tabatabai, Sayyed Abbas

doi:10.5812/ijpr.123826

Cited by 10 publications

(4 citation statements)

References 29 publications

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“…Previous studies have shown that quinazolines could inhibit EGFR tyrosine kinase overexpression by restraining autophosphorylation in EGFR and EGF-stimulated signal transduction (22,23). Also, this scaffold shows antitumor activity by restraining the DNA repair enzyme system (23)(24)(25). As shown in Figure 1, there are some clinical medicines as antitumor agents with quinazoline or bioisosteres of the quinazoline ring, demonstrating the role of quinazoline in cancer therapy (23,26).…”

Section: Introductionmentioning

confidence: 89%

Synthesis, Molecular Dynamics Simulation, and In-vitro Antitumor Activity of Quinazoline-2,4,6-triamine Derivatives as Novel EGFR Tyrosine Kinase Inhibitors

et al. 2023

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Background: Developing a potent and safe scaffold is challenging in anti-cancer drug discovery. Objectives: The study focused on developing novel series of compounds based on the inhibition of epidermal growth factor receptor tyrosine kinase (EGFR-TK) as one of the most promising compounds in cancer therapy. Methods: In this study, a novel series of quinazoline-2,4,6-triamine derivatives were designed and synthesized through intramolecular C-H activation reaction of para-nitro aniline, trichloroacetonitrile, and isocyanides employing a one-pot reaction. Results: The in-vitro antitumor activities of the compounds which showed acceptable inhibitory effects were investigated against breast (MCF-7), lung (A-549), and colon (HT-29) cancer cell lines by employing MTT assay. All compounds had the most negligible cytotoxicity toward normal fibroblast human cell lines. Based on structural and thermodynamics analysis results, it was found that Met 769 is a key residue in interaction with all inhibitors through the formation of hydrogen bonds with high occupancies with the amine group on the quinazoline ring of inhibitors. Also, there was a good consistency between calculated ΔG binding and experimental IC50 values of compounds 10d, 10e, and erlotinib. Conclusions: Compound 10e had an extensive range of antitumor activity on three diverse cell lines comparable with erlotinib and doxorubicin reference drugs. Also, compound 10d showed selective cytotoxicity against cancerous lung cells (A-549). On the other side, computational studies confirmed that Met 769 is a crucial residue in interaction with all inhibitors.

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Section: Introductionmentioning

confidence: 89%

Synthesis, Molecular Dynamics Simulation, and In-vitro Antitumor Activity of Quinazoline-2,4,6-triamine Derivatives as Novel EGFR Tyrosine Kinase Inhibitors

et al. 2023

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“…MODEL online server (University of Basel, Basel, Switzerland) was utilized to estimate the 3D structure of the target protein by the application of the homology modeling method. The validation of the 3D protein structures was subsequently performed using the Ramachandran plot [5].…”

Section: Selection Of Ligands For Inhibitor Designmentioning

confidence: 99%

“…To conduct docking studies, it is necessary for the four potent medications to successfully pass a druglikeness test, which is employed to assess the suitability of a given chemical for usage as a pharmaceutical agent. The assessment of drug-likeness for all compounds was conducted utilizing the SwissADME drug discovery program [5]. The program in question is a rapid, precise, and user-friendly tool for predicting absorption, distribution, metabolism, and excretion processes.…”

Section: Drug-likeness Test -Swissadme Software Based On the Lipinski...mentioning

confidence: 99%

Targeted Drug Designing for Treating Masticatory Myofascial Pain Dysfunction Syndrome: An In Silico Simulation Study

Suresh,

Ramadoss,

Doble

et al. 2024

Cureus

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BackgroundMasticatory Myofascial Pain Dysfunction Syndrome (MMPDS) is a musculoligamentous disorder that shares similarities with temporomandibular joint pain and odontogenic pain. It manifests as dull or aching pain in masticatory muscles, influenced by jaw movement. Computer-aided drug design (CADD) encompasses various theoretical and computational approaches used in modern drug discovery. Molecular docking is a prominent method in CADD that facilitates the understanding of drug-bimolecular interactions for rational drug design, mechanistic studies & the formation of stable complexes with increased specificity and potential efficacy. The docking technique provides valuable insights into binding energy, free energy, and complex stability predictions.

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“…Therefore, this family which regulates tumor cell growth has been expansively investigated as a target for the inhibition of tumor growth (Assenat et al, 2015; Herbst, 2004). In view of the fact that, progress in the development of EGFR inhibitors is one of the most prominent topics of contemporary research in molecularly targeted therapy for the treatment of human cancer (Hynes & Lane, 2005; Nematpour et al, 2022; Tu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and molecular docking studies of novel quinoxaline derivatives as anticancer agents

et al. 2023

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As lung cancer was placed foremost part among other types of cancer in terms of mortality. Recent researches are widely focused on developing multi‐targeted and site‐specific targeted drug designs. In the present study, we designed and developed a series of quinoxaline pharmacophore derivatives as active EGFR inhibitors for the treatment of non‐small cell lung cancer. The compounds were synthesized through a condensation reaction between hexane‐3,4‐dione and methyl 3,4‐diaminobenzoate as a first step. Their structures were confirmed by 1H‐NMR, 13C‐NMR, and HRMS spectroscopic methods. Cytotoxicity (MTT) were applied to determine anticancer activity of the compounds against breast (MCF7), fibroblast (NIH3 T3), and lung (A549) cell lines as EGFR inhibitors. Doxorubicin was used as a reference agent, compound 4i exhibited a significant effect among other derivatives with IC50 = 3.902 ± 0.098 μM value against A549 cell line. The docking study showed that the best position on EGFR receptor could be observed with 4i. From the obtained evaluations of the designed series, compound 4i was a promising agent as EGFR inhibitor for further investigation and evaluation studies in the future.

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Targeting EGFR Tyrosine Kinase: Design, Synthesis and Biological Evaluation of Novel Quinazolinone Derivatives

Cited by 10 publications

References 29 publications

Synthesis, Molecular Dynamics Simulation, and In-vitro Antitumor Activity of Quinazoline-2,4,6-triamine Derivatives as Novel EGFR Tyrosine Kinase Inhibitors

Synthesis, Molecular Dynamics Simulation, and In-vitro Antitumor Activity of Quinazoline-2,4,6-triamine Derivatives as Novel EGFR Tyrosine Kinase Inhibitors

Targeted Drug Designing for Treating Masticatory Myofascial Pain Dysfunction Syndrome: An In Silico Simulation Study

Design, synthesis, and molecular docking studies of novel quinoxaline derivatives as anticancer agents

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