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N ‐Substituted‐4‐phenylphthalazin‐1‐amine‐derived VEGFR‐2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluation studies
Author(s) -
ElAdl Khaled,
Ibrahim MohamedKamal,
Khedr Fathalla,
Abulkhair Hamada S.,
Eissa Ibrahim H.
Publication year - 2021
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.202000219
Subject(s) - sorafenib , chemistry , stereochemistry , cytotoxicity , amine gas treating , docking (animal) , cell culture , lead compound , derivative (finance) , in vitro , biochemistry , biology , organic chemistry , cancer research , medicine , genetics , nursing , hepatocellular carcinoma , economics , financial economics
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 IC 50 = 13.67 ± 1.2, 5.48 ± 0.4, and 7.34 ± 0.6 µM, respectively, which is nearly equipotent to that of sorafenib (IC 50 = 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 IC 50 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 IC 50 value of 0.14 ± 0.02 µM, which is nearly 72% of that of the sorafenib IC 50 value (0.10 ± 0.02 µM). Compounds 7b , 8c , 8b , and 8a exhibited very good activity with IC 50 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.