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

Eissa, Ibrahim H.; El‐Helby, Abdel‐Ghany A.; 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.; El‐Adl, Khaled

doi:10.1016/j.bioorg.2020.104380

Cited by 66 publications

(46 citation statements)

References 41 publications

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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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Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Reagents, solvent, and apparatus used in chemical synthesis were showed in Supplementary data . Compounds 3, 4, 5, 6, 8, 9, 10a-l were prepared according to reported procedures 44–46 , 59–64 . Physical, elemental, and spectral data of the intermediate compounds 10a-l were depicted in Supplementary data .…”

Section: Methodsmentioning

confidence: 99%

Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studies

Alanazi

Elwan

Alsaif

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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There is an urgent need to design new anticancer agents that can prevent cancer cell proliferation even with minimal side effects. Accordingly, two new series of 3-methylquinoxalin-2(1 H )-one and 3-methylquinoxaline-2-thiol derivatives were designed to act as VEGFR-2 inhibitors. The designed derivatives were synthesised and evaluated in vitro as cytotoxic agents against two human cancer cell lines namely, HepG-2 and MCF-7. Also, the synthesised derivatives were assessed for their VEGFR-2inhibitory effect. The most promising member 11e were further investigated to reach a valuable insight about its apoptotic effect through cell cycle and apoptosis analyses. Moreover, deep investigations were carried out for compound 11e using western-plot analyses to detect its effect against some apoptotic and apoptotic parameters including caspase-9, caspase-3, BAX, and Bcl-2. Many in silico investigations including docking, ADMET, toxicity studies were performed to predict binding affinity, pharmacokinetic, drug likeness, and toxicity of the synthesised compounds. The results revealed that compounds 11e, 11g, 12e, 12g, and 12k exhibited promising cytotoxic activities (IC 50 range is 2.1 − 9.8 µM), comparing to sorafenib (IC 50 = 3.4 and 2.2 µM against MCF-7 and HepG2, respectively). Moreover, 11b, 11f, 11g, 12e, 12f, 12g, and 12k showed the highest VEGFR-2 inhibitory activities (IC 50 range is 2.9 − 5.4 µM), comparing to sorafenib (IC 50 = 3.07 nM). Additionally, compound 11e had good potential to arrest the HepG2 cell growth at G2/M phase and to induce apoptosis by 49.14% compared to the control cells (9.71%). As well, such compound showed a significant increase in the level of caspase-3 (2.34-fold), caspase-9 (2.34-fold), and BAX (3.14-fold), and a significant decrease in Bcl-2 level (3.13-fold). For in silico studies, the synthesised compounds showed binding mode similar to that of the reference compound (sorafenib).

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“…All the reagents, chemicals, and apparatus were presented in Supplementary data . Compounds 8 , 9 , 10 , 11 , 12 , 13 , 14 , 16 , 17 , 20a – c , and 21a – c were prepared in accordance with the reported procedures 41 , 42 , 44 , 49 , 50 , 52 .…”

Section: Methodsmentioning

confidence: 99%

“…Based on facts mentioned above and in the extension of our efforts to discover novel molecules with potential anticancer activity 5,[40][41][42][43][44][45][46][47][48] , we design and synthesise a new wave of bis([1, 2, 4]triazolo)[4,3-a:3 0 ,4 0 -c]quinoxaline derivatives having the basic crucial pharmacophoric features of VEGFR-2 inhibitors.…”

Section: Rationale Of Molecular Designmentioning

confidence: 99%

Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers

Alsaif

Taghour

Alanazi

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Herein, a new wave of bis([1, 2, 4]triazolo)[4,3- a :3',4'- c ]quinoxaline derivatives have been successfully designed and synthesised. The synthesised derivatives were biologically investigated for their cytotoxic activities against HepG2 and MCF-7. Also, the tested compounds were further examined in vitro for their VEGFR-2 inhibitory activity. The most promising derivative 23j was further investigated for its apoptotic behaviour in HepG2 cell lines using flow cytometric and western-plot analyses. Additional in-silico studies were performed to predict how the synthesised compounds can bind to VEGFR-2 and to determine the drug-likeness profiling of these derivatives. The results revealed that compounds 23a , 23i , 23j , 23l , and 23n displayed the highest antiproliferative activities against the two cell lines with IC 50 values ranging from 6.4 to 19.4 µM. Furthermore, compounds 23a , 23d , 23h , 23i , 23j , 23l , 23 m , and 23n showed the highest VEGFR-2 inhibitory activities with IC 50 values ranging from 3.7 to 11.8 nM, comparing to sorafenib (IC 50 = 3.12 nM). Moreover, compound 23j arrested the HepG2 cell growth at the G2/M phase and induced apoptosis by 40.12% compared to the control cells (7.07%). As well, such compound showed a significant increase in the level of caspase-3 (1.36-fold), caspase-9 (2.80-fold), and BAX (1.65-fold), and exhibited a significant decrease in Bcl-2 level (2.63-fold).

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

Cited by 66 publications

References 41 publications

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

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

Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studies

Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers

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