Exploration of the VEGFR-2 inhibition activity of phthalazine derivatives: design, synthesis, cytotoxicity, ADMET, molecular docking and dynamic simulation.

Novel phthalazine derivatives were designed, synthesized and evaluated against Hep G2 and MCF-7 as VEGFR-2 inhibitors. In particular, compounds 2g and 4a were found to be the most potent derivatives among all the tested compounds against MCF-7 and Hep G2 cancer cell lines with IC50 values of 0.15 and 0.12 and 0.18 and 0.09 µM respectively. Moreover, compounds 3a, 3c, 5a and 5b displayed excellent anticancer activities against MCF-7 and Hep G2 cancer cell lines. The highly active derivatives 2g, 3a, 3c, 4a, 5a and 5b were evaluated for their inhibitory activities against VEGFR-2. The tested compounds displayed high to low inhibitory activities with IC50 values ranging from 0.148 to 0.892 µM. Among them, compounds 2g and 4a were found to be the most potent derivatives that inhibited VEGFR-2 with IC50 values of 0.148 and 0.196 µM respectively. Compounds 3a, 3c, 5a and 5b exhibited good activity with IC50 values of 0.375, 0.892, 0.548 and 0.331 µM respectively. Sorafenib was used as a reference drug in this study. Molecular modeling studies were carried out for all compounds against the VEGFR-2 active site. The data obtained from biological testing highly correlated with those obtained from molecular modeling studies. Moreover, MD simulation results indicated the stability of ligand-target interaction. Furthermore, our derivatives 2g and 4a showed a good in silico calculated ADMET profile.

Iodoquinazoline-derived VEGFR-2 and EGFRT790M dual inhibitors: Design, synthesis, molecular docking and anticancer evaluations.

Herein, we report the synthesis of a series of new fourteen iodoquinazoline derivatives 7a-c to 13a-e and their evaluation as potential anticancer agents via dual targeting of EGFRT790M and VEGFR-2. The new derivatives were designed according to the target receptors structural requirements. The compounds were evaluated for their cytotoxicity against HepG2, MCF-7, HCT116 and A549 cancer cell lines using MTT assay. Compound 13e showed the highest anticancer activities with IC50 = 5.70, 7.15, 5.76 and 6.50 µM against HepG2, MCF-7, HCT116 and A549 cell lines correspondingly. Compounds 7c, 9b and 13a-d exhibited very good anticancer effects against the tested cancer cell lines. The highly effective six derivatives 7c, 10, 13b, 13c, 13d and 13e were examined against VERO normal cell lines to estimate their cytotoxic capabilities. Our conclusion revealed that compounds 7c, 10, 13b, 13c, 13d and 13e possessed low toxicity against VERO normal cells with IC50 prolonging from 41.66 to 53.99 µM. Also compounds 7a-c to 13a-e were further evaluated for their inhibitory activity against EGFRT790M and VEGFR-2. Also, their ability to bind with both EGFR and VEGFR-2 receptors was examined by molecular modeling. Compounds 13e, 13d, 7c and 13c excellently inhibited VEGFR-2 activity with IC50 = 0.90, 1.00, 1.25 and 1.50 µM respectively. Moreover, Compounds 13e, 7c, 10 and 13d excellently inhibited EGFRT790M activity with IC50 = 0.30, 0.35, 0.45 and 0.47 µM respectively. Finally, our derivatives 7b, 13d and 13e showed good in silico calculated ADMET profile.

Five and six membered heterocyclic rings endowed with azobenzene as dual EGFRT790M and VEGFR-2 inhibitors: design, synthesis, in silico ADMET profile, molecular docking, dynamic simulation and anticancer evaluations.

Novel azobenzene scaffold-joined heterocyclic isoxazole, pyrazole, triazole, and/or triazine moieties have been developed and synthesized utilizing microwave and traditional methods. Our compounds were tested for growth inhibition of A549, MCF-7, HCT-116, and HepG2 tumors by dual targeting the VEGFR-2 and EGFRT790M enzymes. The suggested compound's manner of binding with EGFRT790M and VEGFR-2 active sites was explored through molecular design and MD modeling. The information from the results of the biological screening and the docking studies was highly correlated. The A549 cell line was the one that responded to the novel compound's effects most effectively. Having IC50 values of 5.15, 6.37, 8.44 and 6.23 µM, respectively, 14 was the most effective derivative on the four A549, MCF-7, HCT116 and HepG2 cancer cells. It had greater activity than erlotinib and slightly inferior activities on the tested cell lines than sorafenib, respectively. The cytotoxicity of the most effective derivatives, 5, 6, 10 and 14, was evaluated against typical VERO cell lines. Having IC50 values ranging from 42.32 to 55.20 µM, the results showed that the investigated drugs have modest toxicity against VERO normal cells. Additionally all derivatives were assessed for their dual VEGFR-2 and EGFRT790M inhibitory effects. Among them, derivatives 14, 5 and 10 were established as the greatest inhibitors of VEGFR-2 at IC50 values of 0.95, 1.25 and 1.50 µM correspondingly. As well, derivatives 14, 6, 5 and 10 could inhibit EGFRT790M activity demonstrating strongest effects with IC50 = 0.25, 0.35, 0.40 and 0.50 µM respectively. Furthermore, the ADMET profile was evaluated for compounds 5, 6, 10 and 14 in contrast to reference drugs sorafenib and erlotinib.

Design, Molecular Docking, Synthesis, Anticancer and Anti-Hyperglycemic Assessments of Thiazolidine-2,4-diones Bearing Sulfonylthiourea Moieties as Potent VEGFR-2 Inhibitors and PPARγ Agonists.

Newly designed thiazolidine-2,4-diones 3-7a-c were synthesized, and their anticancer activities were screened against three cancer lines. They showed potent activities against HepG2 compared to the other HCT116 and MCF-7 tumor cell lines. Compounds 7c and 6c were detected as highly effective derivatives against MCF-7 (IC50 = 7.78 and 8.15 µM), HCT116 (IC50 = 5.77 and 7.11 µM) and HepG2 (IC50 = 8.82 and 8.99 µM). The highly effective derivatives 6a-c and 7a-c were tested against VERO normal cell lines. All derivatives were evaluated for their VEGFR-2 inhibitory actions and demonstrated high to low activities, with IC50 values varying from 0.08 to 0.93 µM. Moreover, derivatives 5a-c, 6a-c and 7a-c were assessed to verify their in vitro binding affinities to PPARγ and insulin-secreting activities. Finally, docking studies were performed to explore their affinities and binding modes toward both VEGFR-2 and PPARγ receptors.

Design, synthesis, docking, and anticancer evaluations of phthalazines as VEGFR-2 inhibitors.

Twenty new N-substituted-4-phenylphthalazin-1-amine derivatives were designed, synthesized, and evaluated for their anticancer activities against HepG2, HCT-116, and MCF-7 cells as VEGFR-2 inhibitors. HCT-116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 7f was found to be the most potent derivative among all the tested compounds against the three cancer cell lines, with 50% inhibition concentration, IC50 = 3.97, 4.83, and 4.58 µM, respectively, which is more potent than both sorafenib (IC50 = 9.18, 5.47, and 7.26 µM, respectively) and doxorubicin (IC50 = 7.94, 8.07, and 6.75 µM, respectively). Fifteen of the synthesized derivatives were selected to evaluate their inhibitory activities against VEGFR-2. Compound 7f was found to be the most potent derivative that inhibited VEGFR-2 at an IC50 value of 0.08 µM, which is more potent than sorafenib (IC50 = 0.10 µM). Compound 8c inhibited VEGFR-2 at an IC50 value of 0.10 µM, which is equipotent to sorafenib. Moreover, compound 7a showed very good activity with IC50 values of 0.11 µM, which is nearly equipotent to sorafenib. In addition, compounds 7d, 7c, and 7g possessed very good VEGFR-2-inhibitory activity, with IC50 values of 0.14, 0.17, and 0.23 µM, respectively.

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

In the designed compounds, a new linker was inserted in the form of fragments with verified VEGFR-2 inhibitory potential, including an α,ß-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.

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

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.

Design, Synthesis, In Vitro Anti-cancer Activity, ADMET Profile and Molecular Docking of Novel Triazolo[3,4-a]phthalazine Derivatives Targeting VEGFR-2 Enzyme.

BACKGROUND: Extensive studies were reported in the synthesis of several phthalazine derivatives as promising anticancer agents as potent VEGFR-2 inhibitors. Vatalanib (PTK787) was the first anilinophthalazine published derivative as a potent inhibitor of VEGFR. The discovery of vatalanib as a clinical candidate led to the design and synthesis of different anilinophthalazine derivatives as potent inhibitors for VEGFR-2. The objective of present research work is 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 four different positions. MATERIAL AND METHODS: A correlation between structure and biological activity of our designed phthalazines was established using molecular docking and VEGFR-2 kinase assay. RESULTS AND DISCUSSION: In view of their expected anticancer activity, novel triazolo[3,4-a]phthalazine derivatives 5-6a-o and 3-substituted-bis([1,2,4]triazolo)[3,4-a:4',3'-c]phthalazines 9a-b were designed, synthesized and evaluated for their anti-proliferative activity against two human tumor cell lines HCT-116 human colon adenocarcinoma and MCF-7 breast cancer. It was found that, compound 6o the most potent derivative against both HCT116 and MCF-7 cancer cell lines. Compounds 6o, 6m, 6d and 9b showed the highest anticancer activities against HCT116 human colon adenocarcinoma with IC50 of 7±0.06, 13±0.11, 15±0.14 and 23±0.22 µM respectively while compounds 6o, 6d, 6a and 6n showed the highest anticancer activities against MCF-7 breast cancer with IC50 of 16.98±0.15, 18.2±0.17, 57.54±0.53 and 66.45±0.67 µM respectively. Sorafenib as a highly potent VEGFR-2 inhibitor was used as a reference drug with IC50 of 5.47±0.3 and 7.26±0.3 µM respectively. Nine compounds were further evaluated for their VEGFR-2 inhibitory activity. Compounds 6o, 6m, 6d and 9b emerged as the most active counterparts against VEGFR-2 with IC50 values of 0.1±0.01, 0.15±0.02, 0.28±0.03 and 0.38±0.04 µM, respectively comparable to that of sorafenib (IC50 = 0.1±0.02) µM. Furthermore, molecular docking studies were carried out for all synthesized compounds to investigate their binding pattern and predict their binding affinities towards VEGFR-2 active site. In silico ADMET studies were calculated for the tested compounds. Most of our designed compounds exhibited good ADMET profile. CONCLUSION: The obtained results showed that, the most active compounds could be useful as a template for future design, optimization, adaptation and investigation to produce more potent and selective VEGFR-2 inhibitors with higher anticancer analogs.

Design, Synthesis, Molecular Docking, and Anticancer Activity of Phthalazine Derivatives as VEGFR-2 Inhibitors.

Novel series of phthalazine derivatives 6-11 were designed, synthesized, and evaluated for their anticancer activity against two human tumor cell lines, HCT-116 human colon adenocarcinoma and MCF-7 breast cancer cells, targeting the VEGFR-2 enzyme. Compounds 7a,b and 8b,c showed the highest anticancer activities against both HCT116 human colon adenocarcinoma cells with IC50 of 6.04 ± 0.30, 13.22 ± 0.22, 18 ± 0.20, and 35 ± 0.45 µM, respectively, and MCF-7 breast cancer cells with IC50 of 8.8 ± 0.45, 17.9 ± 0.50, 25.2 ± 0.55, and 44.3 ± 0.49 µM, respectively, in comparison to sorafenib as reference drug with IC50 of 5.47 ± 0.3 and 7.26 ± 0.3 µM, respectively. Eleven compounds in this series were further evaluated for their inhibitory activity against VEGFR-2, where compounds 7a, 7b, 8c, and 8b also showed the highest VEGFR-2 inhibition with IC50 of 0.11 ± 0.01, 0.31 ± 0.03, 0.72 ± 0.08, and 0.91 ± 0.08 µM, respectively, in comparison to sorafenib as reference ligand with IC50 of 0.1 ± 0.02. Furthermore, molecular docking studies were performed for all synthesized compounds to predict their binding pattern and affinity towards the VEGFR-2 active site, in order to rationalize their anticancer activity in a qualitative way.