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

• Published in: Archiv der Pharmazie (Weinheim) 2022-01, Vol.355 (1), p.e2100278-n/a
• Main Authors: El‐Adl, Khaled, Ibrahim, Mohamed K., Khedr, Fathalla, Abulkhair, Hamada S., Eissa, Ibrahim H.
• Format: Article
• Language: English
• Subjects: 4‐phenylphthalazin‐1‐amine; anticancer agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer; Dose-Response Relationship, Drug; Doxorubicin - pharmacology; HCT116 Cells; Hep G2 Cells; Humans; Inhibitory Concentration 50; MCF-7 Cells; molecular docking; Molecular Docking Simulation; Phthalazines - chemical synthesis; Phthalazines - chemistry; Phthalazines - pharmacology; Sorafenib - pharmacology; Structure-Activity Relationship; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; VEGFR‐2 inhibitors
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202100278

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. A series of 20 new N‐substituted‐4‐phenylphthalazin‐1‐amine derivatives were designed, synthesized, and evaluated for their antiproliferative activities against the HepG2, HCT‐116, and MCF‐7 cancer cell lines. Compound 7f was found to be the most potent derivative, being even more potent than sorafenib and doxorubicin. Compound 7f also showed the highest VEGFR‐2‐inhibitory activity.