Design, synthesis, <i>in silico</i> and antiproliferative evaluation of novel pyrazole derivatives as VEGFR‐2 inhibitors

Ravula, Parameshwar; Vamaraju, Harinadha Babu; Paturi, Manichandrika; Chandra, Janivara Nanjunde Gowda Narendra Sharath

doi:10.1002/ardp.201700234

Cited by 18 publications

(13 citation statements)

References 36 publications

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“…[15,20] Many phthalazine derivatives were reported to have VEGFR-2 and EGFR kinase inhibitory activities, with IC 50 values in the nanomolar range; however, compounds were more selective and better inhibitors of VEGFR-2 compared with EGFR. [21,22] Other pharmacophoric heterocycles have been implanted in the structures of recently reported anticancer agents with a VEGFR-2 inhibitory effect, for example, pyrazole [23,24] and pyrimidine. [25,26] The latter were reported to have spatial configurations that enable both to interact with the VEGFR-2 binding site.…”

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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“…Moreover, the same compound exhibited the highest VEGFR-2 inhibitory activity with an IC 50 value of 1.89 mM. 166 The in vitro and in vivo results collectively suggest that 174 (Fig. 7), a new type of signal transducer and activator of transcription (STAT)3 inhibitors based on structural modications on shikonin scaffold, guided by computational modeling, may serve as a promising lead compound for the further development of potential therapeutic anti-neoplastic agents.…”

Section: Computer-aided Synthesis Of Compoundsmentioning

confidence: 91%

“…Chimento et al, 145 reported the synthesis of some new titanocene and half-titanocene compounds having a methyl group on the carbon 6 and a methoxy-naphthyl group as substituent of the cyclopentadienyl. Moreover, the IC 50 values of the most active compounds (i.e., [164][165][166] and of cisplatin have been calculated, evidencing that these new complexes 164-166 (IC 50 value of 85.26, 49.16 and 129.8 mM respectively for MCF-7) exerted antiproliferative effect on MCF-7 BC cells, via inhibiting important DNA-metabolizing enzymes, that is, topoisomerase I and II (Table 7).…”

Section: The Titanocene Functional Groupmentioning

confidence: 93%

Current research on anti-breast cancer synthetic compounds

et al. 2018

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“…After 3 h incubation at 37 °C, 100 μL of DMSO was added to each well, and the plate was agitated for 1 min. The absorbance was read at 570 nm with a multi‐well plate reader (Victor3, PerkinElmer), and IC 50 values were calculated .…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Docking Studies of Novel Dimethyl Triazene Incorporated Thiazolyl Pyrazolines for Anticancer Activity

Ravula

Vamaraju

Paturi

et al. 2018

Journal of Heterocyclic Chem

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A novel series of dimethyl triazene incorporated thiazolyl pyrazolines have been designed on the basis of hybridization and also in support with combi‐targeting approach. The designed compounds were synthesized through facile synthetic methods, and the compounds were confirmed by 1H NMR, 13C NMR, MS, and elemental analysis. Further, compounds were screened for in vitro anticancer activity against human breast cancer (MCF‐7) and human colon cancer (HT‐29) cell lines by MTT assay. Among all the tested compounds, compound 9b showed highest activity against both the cell lines in comparison with reference drug, Cisplatin. In addition, the synthesized compounds were docked into VEGFR‐2 kinase (PDB code: 2XIR) to explore their binding interactions at the active site. The compounds showed essential key interactions as that of known VEGFR‐2 inhibitors, and hence, the synthesized compounds may be considered as molecular scaffolds for anticancer activity.

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Design, synthesis, in silico and antiproliferative evaluation of novel pyrazole derivatives as VEGFR‐2 inhibitors

Cited by 18 publications

References 36 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

Current research on anti-breast cancer synthetic compounds

Design, Synthesis, and Docking Studies of Novel Dimethyl Triazene Incorporated Thiazolyl Pyrazolines for Anticancer Activity

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