Design, synthesis, molecular docking, in silico ADMET profile and anticancer evaluations of sulfonamide endowed with hydrazone-coupled derivatives as VEGFR-2 inhibitors

et al. 2021

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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.

Section: Introductionmentioning

confidence: 99%

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

Khedr

et al. 2021

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“…Anastrozole containing a 1,2, 4-triazole ring is used in the treatment of postmenopausal women with estrogen-responsive breast cancer. [24] On the basis of the earlier findings and in continuation of our previous research in anticancer agents, [25][26][27][28][29][30][31][32][33][34][35] especially DNA intercalators, [36][37][38][39] we reported herein DNA-binding and docking studies of a new series of [1,2,4]triazolo [4,3-c]quinazoline derivatives as anticancer agents.…”

Section: Introductionmentioning

confidence: 85%

“…On the basis of the earlier findings and in continuation of our previous research in anticancer agents, [ 25–35 ] especially DNA intercalators, [ 36–39 ] we reported herein DNA‐binding and docking studies of a new series of [1,2,4]triazolo[4,3‐ c ]quinazoline derivatives as anticancer agents.…”

Section: Introductionmentioning

confidence: 90%

Design, synthesis, in silico ADMET, docking, and antiproliferative evaluations of [1,2,4]triazolo[4,3‐c]quinazolines as classical DNA intercalators

Alesawy

et al. 2022

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Eleven novel [1,2,4]triazolo [4,3-c]quinazolines were designed, synthesized, and evaluated against HepG2 and HCT-116 cells. The molecular design was performed to investigate the binding mode of the proposed compounds with the DNA active site. The data obtained from biological testing highly correlated with that obtained from molecular modeling. HCT-116 was found to be the most sensitive cell line to the influence of the new derivatives. In particular, compounds 6 f and 6 e were found to be the most potent derivatives over all the tested compounds against the two HepG2 and HCT116 cancer cell lines, with IC 50 = 23.44 ± 2.9, 12.63 ± 1.2, and 25.80 ± 2.1, and 14.32 ± 1.5 µM, respectively. Although compounds 6 f and 6 e displayed less activity than doxorubicin (IC 50 = 7.94 ± 0.6 and 8.07 ± 0.8 µM, respectively), both could be useful as a template for future design, optimization, and investigation to produce more potent anticancer analogs. The most active derivatives 6 a , 6 c , 6 e , and 6 f were evaluated for their DNA-binding activities. Compound 6 f displayed the highest binding affinity. This compound potently intercalates DNA at a decreased IC 50 value (54.08 µM). Compounds 6 a , 6 c , and 6 e exhibited good DNA-binding affinities, with IC 50 values of 79.35, 84.08, and 59.35 µM, respectively. Furthermore, ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles were calculated for the four most active compounds in comparison to doxorubicin as a reference drug. Our derivatives 6 a , 6 c , 6 e , and 6 f displayed very good in-silico-predicted ADMET profiles. Doxorubicin violates three of Lipinski's rules, our derivatives 6 a , 6 c , 6 e , and 6 f do not violate any rule.

“…Here, we present DNA binding and docking studies of a new series of [1,2,4]triazolo[4,3‐c]quinazoline derivatives as anticancer agents, based on our earlier study in anticancer drugs, [ 8–22 ] especially DNA intercalators. [ 20,23–26 ]…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative evaluations of triazoloquinazolines as classical DNA intercalators: Design, synthesis, ADMET profile, and molecular docking

Alesawy

et al. 2022

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Novel triazoloquinazolines were designed and synthesized and evaluated as anticancer agents against HepG2 and HCT-116 cells. The biological testing data corresponded well to those of the molecular docking studies. The HCT-116 cell line was most affected due to the actions of our derivatives. Derivative 7 a was the most potent one against both HepG2 and HCT116 cells, with IC 50 = 7.98 and 5.57 µM, respectively. This compound showed anticancer activity that was nearly equipotent to that of doxorubicin against HepG2 cells, but higher than that of doxorubicin against HCT116 cells (IC 50 = 7.94 and 8.07 µM, respectively). Compounds 8, 7 b , and 6 f showed excellent anticancer activities against both the HCT116 and HepG2 cell lines. The highly active compounds 6 f , 7 a , 7 b , and 8 were evaluated for their DNAbinding activities. Compounds 7 a and 8 showed the highest binding activities. These derivatives potently intercalate in DNA, at IC 50 values of 42.90 and 48.13 µM, respectively. Derivatives 6 f and 7 b showed good DNA-binding activities, with IC 50 values of 54.24 and 50.56 µM, respectively. Furthermore, in silico calculated AD-MET profiles were established for our four highly active derivatives, in comparison to doxorubicin. Our derivatives 6 f , 7 a , 7 b , and 8 showed a very good ADMET profile.Compounds 6 f , 7 a , 7 b , and 8 follow Lipinski's rules, while doxorubicin violates three of these rules.