New quinoline and isatin derivatives as apoptotic VEGFR-2 inhibitors: design, synthesis, anti-proliferative activity, docking, ADMET, toxicity, and MD simulation studies

Abstract

New quinoline and isatin derivatives having the main characteristics of VEGFR-2 inhibitors was synthesised. The antiproliferative effects of these compounds were estimated against A549, Caco-2, HepG2, and MDA-MB-231. Compounds 13 and 14 showed comparable activities with doxorubicin against the Caco-2 cells. These compounds strongly inhibited VEGFR-2 kinase activity. The cytotoxic activities were evaluated against Vero cells. Compound 7 showed the highest value of safety and selectivity. Cell migration assay displayed the ability of compound 7 to prevent healing and migration abilities in the cancer cells. Furthermore, compound 7 induced apoptosis in Caco-2 through the expressive down-regulation of the apoptotic genes, Bcl2, Bcl-xl, and Survivin, and the upregulation of the TGF gene. Molecular docking against VEGFR-2 emerged the interactions of the synthesised compounds in a similar way to sorafenib. Additionally, seven molecular dynamics simulations studies were applied and confirmed the stability of compound 13 in the active pocket of VEGFR-2 over 100 ns.

Novel Benzoic Acid Derivatives Bearing Quinazolin‐4(3H)‐one Ring: Synthesis, Characterization, and Inhibition Effects on α‐Glucosidase and α‐Amylase

“…Combining the molecules from two or more compound classes into a single molecule by chemical reactions is known as molecular hybridization. Molecular hybridization is a good drug design strategy [29] . Hybrid molecules obtained by combining molecules from two or more biologically active compound classes in a single molecule can be more effective and selective.…”

“…Molecular hybridization is a good drug design strategy. [29] Hybrid molecules obtained by combining molecules from two or more biologically active compound classes in a single molecule can be more effective and selective. The interest of chemists in the synthesis of new hybrid molecules continues to grow because of their biological and pharmaceutical properties.…”

1-Benzyl-5-bromo-3-hydrazonoindolin-2-ones as Novel Anticancer Agents: Synthesis, Biological Evaluation and Molecular Modeling Insights

“…After the FDA’s approval of the VEGFR-2 inhibitor Sunitinib, medicinal chemists have paid special attention to the identification of new isatin-based anti-cancer candidates targeting VEGFR-2 kinase [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. Our research team has recently reported several VEGFR-2 inhibitors based on the isatin scaffold [ 45 , 46 , 47 , 48 , 49 , 50 ]. In 2020, we developed a new set of triazolo[3,4- b ]thiadiazine—isatin hybrids with promising anti-angiogenic activities [ 46 ].…”

“…Compound I remarkably reduced the developed blood vessels; in addition, it was not toxic for the chick embryos. In the last year, another small set of 2,4-thiazolidindione—isatin hybrids with promising anticancer and VEGFR-2 inhibitory activities were reported [ 47 , 48 , 49 ]. Compound II ( Figure 1 ) revealed good anti-proliferative activities toward breast, lung, and colon cancer cell lines.…”

The Anticancer Effect of a Novel Quinoline Derivative 91b1 through Downregulation of Lumican

“…With the development of cytobiology and molecular biology, the essential principles of tumorigenesis, invasion, migration, and metastasis induced by quinoline derivatives have been further explained. Antitumor mechanisms of quinoline derivatives include alkylating DNA [ 14 ], inhibiting c-Met kinase [ 15 ], epidermal growth factor receptor (EGFR) [ 16 ], and vascular endothelial growth factor (VEGF) [ 16 , 17 , 18 ]. Some were also proven to inhibit P-glycoprotein [ 19 ].…”