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

Abstract

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.

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

“…The adopted synthetic strategies for the preparation of target compounds (4-7) are shown in Schemes 1 and 2. The synthesis was initiated by cyclocondensation of 2-benzoylbenzoic acid (1) with hydrazine hydrate to afford the corresponding 4-phenylphthalazin-1(2H)-one [11,47,48] (2), which underwent chlorination by reaction with phosphorous oxychloride [11,33,49] to afford 1-chloro-4phenylphthalazine (3). The chloro derivative 3 was heated under reflux with the 4-aminoacetophenone to afford the corresponding acetyl derivative 4.…”

“…(iv) a terminal hydrophobic moiety to occupy the allosteric hydrophobic pocket. [11] Over the last two decades, a number of VEGFR-2 inhibitors have demonstrated success as targeted anticancer therapeutics. Among these, sorafenib (I), the 1,4-disubstituted phthalazine derivatives, vatalanib (II), AAC789 (III), AMG 900 (IV), and IM-023911 (V) revealed potent inhibitory activity against VEGFR-2 in nanomolar levels of IC 50 .…”

“…[12,13] Sorafenib is an FDA-approved antiangiogenic drug that shares the above pharmacophoric features. [14] The phthalazine ring is a vital pharmacophoric scaffold present in the core structures of many anticancer molecules [11,[15][16][17][18][19] with potent activity against hepatocellular carcinoma, [18] colon cancer, [11] and breast cancer, [19] and as degraders of VEGFR-2. [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.…”

New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells

“…Thienyl-based VEGFR-2 inhibitors have been published, such as chalcone derivatives with thienyl moieties, which showed considerable VEGFR-2 inhibitory activities as well as activities against HUVEC cells as an angiogenesis cell model [ 14 ]. Several works about new VEGFR-2 inhibitors were disclosed, which indicate the clinical potential and importance of this research field [ 39 , 40 , 41 ]. Compound 1c also inhibited the receptor tyrosine kinase c-Kit, which is a cell growth promoting factor and a relapse risk enhancer in hepatoma [ 42 ].…”

In vivo‐ and in silico‐driven identification of novel synthetic quinoxalines as anticonvulsants and AMPA inhibitors

“…Also, the possible underlying mechanisms of the highest effective compounds were investigated in silico to rationalize their antagonistic activity against AMPA receptors. Finally, ADMET profiles were also evaluated to the best effective derivatives to evaluate [62,63] The InChI codes of the investigated compounds, together with some biological activity data, are provided as Supporting Information. PTZ-induced convulsion model.…”