Design, synthesis, molecular docking and anticancer evaluations of 5-benzylidenethiazolidine-2,4-dione derivatives targeting VEGFR-2 enzyme

El‐Adl, Khaled; El‐Helby, Abdel‐Ghany A.; Sakr, Helmy; Eissa, Ibrahim H.; El‐Hddad, Sanadelaslam S. A.; Shoman, Fatma M.I.A.

doi:10.1016/j.bioorg.2020.104059

Cited by 70 publications

(60 citation statements)

References 42 publications

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“…N ‐Substituted‐4‐phenylphthalazin‐1‐amine derivatives have the essential pharmacophoric features of VEGFR‐2 inhibitors [ 22,39‐44 ] (Figure 1), which include the following: First, there exists a six‐membered heteroaromatic ring, phthalazine, as a central aryl moiety, substituted with phenyl ring, as a hydrophobic portion, forming the 4‐phenylphthalazine scaffold. Second, the target phenyl group at position‐4 is used to replace pyridine and N ‐methylpicolinamide moieties of vatalanib and sorafenib (Figures 2 and 3), respectively.…”

Section: Resultsmentioning

confidence: 99%

“…In continuation of our efforts to obtain new anticancer agents, [ 37‐43 ] the goal of the present work was the synthesis of new agents with the same essential pharmacophoric features of the reported and clinically used VEGFR‐2 inhibitors (e.g., vatalanib and sorafenib). The main core of our molecular design rationale comprised bioisosteric modification strategies of VEGFR‐2 inhibitors at the four different pharmacophoric positions (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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N‐Substituted‐4‐phenylphthalazin‐1‐amine‐derived VEGFR‐2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluation studies

El‐Adl

Ibrahim

Khedr

et al. 2020

Archiv der Pharmazie

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In accordance with the significant impetus of the discovery of potent vascular endothelial growth factor receptor 2 (VEGFR‐2) inhibitors, herein, we report the design, synthesis, and anticancer evaluation of 12 new N‐substituted‐4‐phenylphthalazin‐1‐amine derivatives against HepG2, HCT‐116, and MCF‐7 cells as VEGFR‐2 inhibitors. The results of the cytotoxicity investigation indicated that HCT‐116 and MCF‐7 were the most sensitive cell lines to the influence of the newly synthesized derivatives. In particular, compound 7a was found to be the most potent derivative among all the tested compounds against the three cancer cell lines, HepG2, HCT116, and MCF‐7, with IC50 = 13.67 ± 1.2, 5.48 ± 0.4, and 7.34 ± 0.6 µM, respectively, which is nearly equipotent to that of sorafenib (IC50 = 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively). All synthesized derivatives, 4a,b−8a−c, were evaluated for their inhibitory activities against VEGFR‐2. The tested compounds displayed high to low inhibitory activity, with IC50 values ranging from 0.14 ± 0.02 to 9.54 ± 0.85 µM. Among them, compound 7a was found to be the most potent derivative that inhibited VEGFR‐2 at an IC50 value of 0.14 ± 0.02 µM, which is nearly 72% of that of the sorafenib IC50 value (0.10 ± 0.02 µM). Compounds 7b, 8c, 8b, and 8a exhibited very good activity with IC50 values of 0.18 ± 0.02, 0.21 ± 0.03, 0.24 ± 0.02, and 0.35 ± 0.04 µM, respectively. Molecular modeling studies were carried out for all compounds against the VEGFR‐2 active site. The data obtained from biological testing highly correlated with that obtained from molecular modeling studies. However, these modifications led to new phthalazine derivatives with higher VEGFR‐2 inhibitory activities than vatalanib and which are nearly equipotent to sorafenib.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

N‐Substituted‐4‐phenylphthalazin‐1‐amine‐derived VEGFR‐2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluation studies

El‐Adl

Ibrahim

Khedr

et al. 2020

Archiv der Pharmazie

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“…Novel thiazolidine 2,4-diones reported by Khaled et al, have also demonstrated excellent in vitro VEGFR-2 inhibition and MCF-7 tumor growth suppression. Moreover, in silico VEGFR-2 binding results of synthesized ligands were very well correlated with in vitro antiproliferative activities [ 26 ]. Figure 1 depicts some recently developed in silico VEGFR-2 inhibitors that eventually evolved into potential in vitro anti-tumor agents [ 22 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Rational Design of New Appended 1,2,3-Triazole-uracil Ensembles as Promising Anti-Tumor Agents via In Silico VEGFR-2 Transferase Inhibition

et al. 2021

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Angiogenesis inhibition is a key step towards the designing of new chemotherapeutic agents. In a view to preparing new molecular entities for cancer treatment, eighteen 1,2,3-triazole-uracil ensembles 5a–r were designed and synthesized via the click reaction. The ligands were well characterized using 1H-, 13C-NMR, elemental analysis and ESI-mass spectrometry. The in silico binding propinquities of the ligands were studied sequentially in the active region of VEGFR-2 using the Molegro virtual docker. All the compounds produced remarkable interactions and potentially inhibitory ligands against VEGFR-2 were obtained with high negative binding energies. Drug-likeness was assessed from the ADME properties. Cytotoxicity of the test compounds was measured against HeLa and HUH-7 tumor cells and NIH/3T3 normal cells by MTT assay. Compound 5h showed higher growth inhibition activity than the positive control, 5-fluorouracil (5-FU), against both HeLa and HUH-7 cells with IC50 values of 4.5 and 7.7 μM respectively. Interestingly, the compounds 5a–r did not show any cytotoxicity towards the normal cell lines. The results advance the position of substituted triazoles in the area of drug design with no ambiguity.

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“…[ 21,22 ] Sorafenib (Nexavar®; IV ; (Figure 1) also is a potent VEGFR‐2 inhibitor and has been approved as an anti‐angiogenic drug. [ 23–25 ] Our reported compounds V [ 19 ] and VI [ 20 ] encourage us to synthesize new derivatives with the hydrophobic electron‐withdrawing mono‐, chloro‐, and/or dichlorobenzylidene instead of unsubstituted ( V ) or the hydrophobic electron‐donating methoxybenzylidenes ( VI ), respectively, to study the effect of these modifications on the activity.…”

Section: Introductionmentioning

confidence: 99%

“…A study reported by Shah et al, [12] showed that TZD derivative ciglitazone (I) ( Figure 1) significantly decreased the VEGF production in human granulose cells in an in vitro model. Extensive studies were reported in the synthesis of several 5-benzylidenethiazolidine-2,4-dione derivatives as potent anticancer agents [13][14][15][16][17][18][19][20] and potent VEGFR-2 inhibitors, for example, compound II. [2,12] Owing to the importance of VEGFR-2 in angiogenesis, this receptor is the most vital target in anti-angiogenic therapy against cancer.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, molecular docking, anticancer evaluations, and in silico pharmacokinetic studies of novel 5‐[(4‐chloro/2,4‐dichloro)benzylidene]thiazolidine‐2,4‐dione derivatives as VEGFR‐2 inhibitors

El‐Adl

El‐Helby

Sakr

et al. 2020

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The anticancer activity of novel thiazolidine‐2,4‐diones was evaluated against HepG2, HCT‐116, and MCF‐7 cells. MCF‐7 was the most sensitive cell line to the cytotoxicity of the new derivatives. In particular, compounds 18, 12, 17, and 16 were found to be the most potent derivatives over all the tested compounds against the cancer cell lines HepG2, HCT116, and MCF‐7, with IC50 = 9.16 ± 0.9, 8.98 ± 0.7, 5.49 ± 0.5 µM; 9.19 ± 0.5, 8.40 ± 0.7, 6.10 ± 0.4 µM; 10.78 ± 1.2, 8.87 ± 1.5, 7.08 ± 1.6 µM; and 10.87 ± 0.8, 9.05 ± 0.7, 7.32 ± 0.4 µM, respectively. Compounds 18 and 12 have nearly the same activities as sorafenib (IC50 = 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively), against HepG2 cells, but slightly lower activity against HCT116 cells and slightly higher activity against the MCF‐7 cancer cell line. Also, these compounds displayed lower activities than doxorubicin against HepG2 and HCT‐116 cells but higher activity against MCF‐7 cells (IC50 = 7.94 ± 0.6, 8.07 ± 0.8, and 6.75 ± 0.4 µM, respectively). In contrast, compounds 17 and 16 exhibited lower activities than sorafenib against HepG2 and HCT116 cells, but nearly equipotent activity against the MCF‐7 cancer cell line. Also, these compounds displayed lower activities than doxorubicin against the three cell lines. All the synthesized derivatives 7–18 were evaluated for their inhibitory activities against VEGFR‐2. The tested compounds displayed high to medium inhibitory activity, with IC50 values ranging from 0.17 ± 0.02 to 0.27 ± 0.03 µM. Compounds 18, 12, 17, and 16 potently inhibited VEGFR‐2 at IC50 values of 0.17 ± 0.02, 0.17 ± 0.02, 0.18 ± 0.02, and 0.18 ± 0.02 µM, respectively, which are nearly more than half of that of the IC50 value for sorafenib (0.10 ± 0.02 µM).

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Design, synthesis, molecular docking and anticancer evaluations of 5-benzylidenethiazolidine-2,4-dione derivatives targeting VEGFR-2 enzyme

Cited by 70 publications

References 42 publications

N‐Substituted‐4‐phenylphthalazin‐1‐amine‐derived VEGFR‐2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluation studies

N‐Substituted‐4‐phenylphthalazin‐1‐amine‐derived VEGFR‐2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluation studies

Synthesis and Rational Design of New Appended 1,2,3-Triazole-uracil Ensembles as Promising Anti-Tumor Agents via In Silico VEGFR-2 Transferase Inhibition

Design, synthesis, molecular docking, anticancer evaluations, and in silico pharmacokinetic studies of novel 5‐[(4‐chloro/2,4‐dichloro)benzylidene]thiazolidine‐2,4‐dione derivatives as VEGFR‐2 inhibitors

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