Design, synthesis, docking, ADMET profile, and anticancer evaluations of novel thiazolidine‐2,4‐dione derivatives as VEGFR‐2 inhibitors

Abstract

The anticancer activity of novel thiazolidine‐2,4‐diones was evaluated against HepG2, HCT‐116, and MCF‐7 cells. Among the tested cancer cell lines, HCT‐116 was the most sensitive one to the cytotoxic effect of the new derivatives. In particular, compounds 18, 11, and 10 were found to be the most potent derivatives among all the tested compounds against the HepG2, HCT‐116, and MCF‐7 cancer cell lines, with IC50 values ranging from 38.76 to 53.99 µM. The most active antiproliferative derivatives (7–14 and 15–19) were subjected to further biological studies to evaluate their inhibitory potentials against VEGFR‐2. The tested compounds displayed a good‐to‐medium inhibitory activity, with IC50 values ranging from 0.26 to 0.72 µM. Among them, compounds 18, 11, and 10 potently inhibited VEGFR‐2 at IC50 values in the range of 0.26–0.29 µM, which are nearly three times that of the sorafenib IC50 value (0.10 µM). Although our derivatives showed lower activities than the reference drug, they 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. The ADMET profile showed that compounds 18, 11, and 10 do not violate any of Lipinski's rules and have a comparable intestinal absorptivity in humans. Also, the new derivatives could not inhibit cytochrome P3A4. Unlike sorafenib and doxorubicin, compounds 18, 11, and 10 are expected to have prolonged dosing intervals. Moreover, compounds 10 and 18 displayed a wide therapeutic index and higher selectivity against cancer cells as compared with their cytotoxicity against normal cells.

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

“…[28,29] 1.1 | Rationale and aim of the work Over the last few years, our research group members were interested in the construction and evaluation of heterocyclic molecules with expected biological activity, particularly those with anticancer activity. [30][31][32][33][34][35][36] The objective of this study is to develop a novel inhibitor that has the potential to interact with the VEGFR-2 protein. Accordingly, the above-mentioned facts have encouraged us to design novel N-substituted-4-phenylphthalazin-1-amine derivatives linked with fragments of verified VEGFR-2 inhibitory potentials, including an α, β-unsaturated ketonic fragment, [28,29] pyrazole, [23,24] and pyrimidine, to investigate the anticancer and VEGFR-2 inhibitory potential of the designed compounds.…”

Rationale design, synthesis, cytotoxicity evaluation, andin silicomechanistic studies of novel 1,2,3-triazoles with potential anticancer activity

“…The VEGFR-2 receptor, the proposed biological target for the new molecules, has been reported to be overexpressed in the majority of the tested cancer cells including breast, colorectal, prostate, leukemia, and lung cancers. 42–46…”

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

“…The starting and intermediate derivatives, thiazolidine-2,4-dione (1), 5-benzylidenethiazolidine-2,4-dione (2a,b) [22,24] and 2-chloro-N-(4-sulfamoylphenyl)acetamide [63], were synthesized according to the reported procedures.…”

“…Rosiglitazone (I) and pioglitazone (II) suppress the expression of VEGF via a responsive element for PPAR-γ in the VEGF gene promoter [15]. However, several TZD derivatives, e.g., ciglitazone III and compound (IV), have also been reported to be effective as antiangiogenic and antineoplastic agents through VEGFR-2 targeting [16][17][18][19][20][21][22][23][24] by reducing the in vitro model of VEGF production [20]. The VEGFR-2 receptor is the most important antiangiogenic target due to its crucial role in cancer angiogenesis.…”