Design, synthesis, and anti-proliferative evaluation of new quinazolin-4(3H)-ones as potential VEGFR-2 inhibitors

El‐Adl, Khaled; El‐Helby, Abdel‐Ghany A.; Ayyad, Rezk R.; Mahdy, Hazem A.; Khalifa, Mohamed M.; El-Nagar, H. A.; Mehany, Ahmed B. M.; Metwaly, Ahmed M.; Elhendawy, Mostafa A.; Radwan, Mohamed M.; ElSohly, Mahmoud A.; Eissa, Ibrahim H.

doi:10.1016/j.bmc.2020.115872

Cited by 59 publications

(38 citation statements)

References 64 publications

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“…[28,29] 1.1 | Rationale and aim of the work Over the last few years, our research group members were interested in the construction and evaluation of heterocyclic molecules with expected biological activity, particularly those with anticancer activity. [30][31][32][33][34][35][36] The objective of this study is to develop a novel inhibitor that has the potential to interact with the VEGFR-2 protein. Accordingly, the above-mentioned facts have encouraged us to design novel N-substituted-4-phenylphthalazin-1-amine derivatives linked with fragments of verified VEGFR-2 inhibitory potentials, including an α, β-unsaturated ketonic fragment, [28,29] pyrazole, [23,24] and pyrimidine, to investigate the anticancer and VEGFR-2 inhibitory potential of the designed compounds.…”

Section: Introductionmentioning

confidence: 99%

Phthalazine‐based VEGFR‐2 inhibitors: Rationale, design, synthesis, in silico, ADMET profile, docking, and anticancer evaluations

Khedr

Ibrahim

Eissa

et al. 2021

Archiv der Pharmazie

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In the designed compounds, a new linker was inserted in the form of fragments with verified VEGFR‐2 inhibitory potential, including an α,β‐unsaturated ketonic fragment, pyrazole, and pyrimidine. Also, new distal hydrophobic moieties were attached to these linkers that are expected to increase the hydrophobic interaction with VEGFR‐2 and, consequently, the affinity. These structural optimizations have led us to identify the novel dihydropyrazole derivative 6e as a promising hit molecule. All the new derivatives were evaluated to assess their anticancer activity against three human cancer cell lines, including HepG2, HCT‐116, and MCF‐7. The results of the in vitro anticancer evaluation study revealed the moderate to excellent cytotoxicity of 6c, 6e, 6g, and 7b, with IC50 values in the low micromolar range. The inhibitory activity of VEGFR‐2 was investigated for 16 of the designed compounds. The enzyme assay results of the new compounds were compared with those of sorafenib as a reference VEGFR‐2 inhibitor. The obtained results demonstrated that our derivatives are potent VEGFR‐2 inhibitors. The most potent derivatives 6c, 6e, 6g, and 7b showed IC50 values in the range of 0.11–0.22 µM. Molecular docking and pharmacokinetic studies were also conducted to rationalize the VEGFR‐2 inhibitory activity and to evaluate the ability of the most potent derivatives to be developed as good drug candidates.

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Section: Introductionmentioning

confidence: 99%

Phthalazine‐based VEGFR‐2 inhibitors: Rationale, design, synthesis, in silico, ADMET profile, docking, and anticancer evaluations

Khedr

Ibrahim

Eissa

et al. 2021

Archiv der Pharmazie

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“…These approaches are essential contributors to the development of new bioactive agents [2][3][4][5][6][7][8]. Computer-assisted drug design has been applied in drug discovery [9][10][11], computational chemistry [12,13], toxicity prediction [14][15][16], ADMET assessment [17][18][19], molecular modeling [20], molecular design [21,22], and rational drug design [23][24][25][26][27]. All these techniques have great popularity and have been used in both academic fields in addition to the pharmaceutical industries [28].…”

Section: Introductionmentioning

confidence: 99%

In Silico Exploration of Potential Natural Inhibitors against SARS-Cov-2 nsp10

et al. 2021

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In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (SAM), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. The docking studies picked 48, 182, 220, 221, and 284. While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182. Finally, a density-functional theory (DFT) study suggested vidarabine (182) to be the most relevant SARS-Cov-2 nsp10 inhibitor.

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“…In the present work, the binding potential of humuleneglucoside (1) against four SARS-CoV-2 proteins has been investigated using the Molecular Operating Environment (MOE) [50][51][52][53]. e selected SARS-CoV-2 proteins are (i) COVID-19 main protease (M pro ) (PDB ID: 6lu7, resolution: 2.16Å), (ii) nonstructural protein (nsp) 10 (PDB ID: 6W4H, resolution: 1.80Å), (iii) RNA-dependent RNA polymerase (PDB ID: 7BV2, resolution: 2.50Å), and (iv) SARS-CoV-2 helicase (PDB ID: 5RMM, resolution: 2.20Å).…”

Section: Molecular Dockingmentioning

confidence: 99%

Comprehensive In Silico Screening of the Antiviral Potentialities of a New Humulene Glucoside from Asteriscus hierochunticus against SARS-CoV-2

Imieje

Zaki

Metwaly

et al. 2021

Journal of Chemistry

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Chromatographic fractionation of the methanolic extract of Asteriscus hierochunticus whole plant led to the identification of a new humulene glucoside (1). The chemical structure of the isolated compound was elucidated by IR, 1D, 2D NMR, and HRESIMS data analysis to be (-)-(2Z,6E,9E)8α-hydroxy-2,6,9-humulatrien-1(12)-olide. In this study, we report the in silico binding affinities of 1 against four different SARS-CoV-2 proteins (COVID-19 main protease (PDB ID: 6lu7), nonstructural protein (PDB ID: 6W4H), RNA-dependent RNA polymerase (PDB ID: 7BV2), and SARS-CoV-2 helicase (PDB ID: 5RMM)). The isolated compound showed excellent binding affinity values (ΔG) of −21.65, −20.05, −28.93, and −21.73 kcal/mol, respectively, against the target proteins compared to the cocrystallized ligands that exhibited ΔG values of −23.75, −17.65, −23.57, and −15.30 kcal/mol, respectively. Further in silico investigations of the isolated compound (1) for its ADMET and toxicity profiles revealed excellent drug likeliness. On the other hand, the results obtained from in vitro antitrypanosomal, antileishmanial, and antimalarial activities of (1) were not promising.

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Design, synthesis, and anti-proliferative evaluation of new quinazolin-4(3H)-ones as potential VEGFR-2 inhibitors

Cited by 59 publications

References 64 publications

Phthalazine‐based VEGFR‐2 inhibitors: Rationale, design, synthesis, in silico, ADMET profile, docking, and anticancer evaluations

Phthalazine‐based VEGFR‐2 inhibitors: Rationale, design, synthesis, in silico, ADMET profile, docking, and anticancer evaluations

In Silico Exploration of Potential Natural Inhibitors against SARS-Cov-2 nsp10

Comprehensive In Silico Screening of the Antiviral Potentialities of a New Humulene Glucoside from Asteriscus hierochunticus against SARS-CoV-2

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