Design, Synthesis, Molecular Docking, and Anticancer Activity of Phthalazine Derivatives as VEGFR‐2 Inhibitors

Abstract

Novel series of phthalazine derivatives 6-11 were designed, synthesized, and evaluated for their anticancer activity against two human tumor cell lines, HCT-116 human colon adenocarcinoma and MCF-7 breast cancer cells, targeting the VEGFR-2 enzyme. Compounds 7a,b and 8b,c showed the highest anticancer activities against both HCT116 human colon adenocarcinoma cells with IC of 6.04 ± 0.30, 13.22 ± 0.22, 18 ± 0.20, and 35 ± 0.45 μM, respectively, and MCF-7 breast cancer cells with IC of 8.8 ± 0.45, 17.9 ± 0.50, 25.2 ± 0.55, and 44.3 ± 0.49 μM, respectively, in comparison to sorafenib as reference drug with IC of 5.47 ± 0.3 and 7.26 ± 0.3 μM, respectively. Eleven compounds in this series were further evaluated for their inhibitory activity against VEGFR-2, where compounds 7a, 7b, 8c, and 8b also showed the highest VEGFR-2 inhibition with IC of 0.11 ± 0.01, 0.31 ± 0.03, 0.72 ± 0.08, and 0.91 ± 0.08 μM, respectively, in comparison to sorafenib as reference ligand with IC of 0.1 ± 0.02. Furthermore, molecular docking studies were performed for all synthesized compounds to predict their binding pattern and affinity towards the VEGFR-2 active site, in order to rationalize their anticancer activity in a qualitative way.

5‐(4‐Methoxybenzylidene)thiazolidine‐2,4‐dione‐derived VEGFR‐2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluations

“…5‐(4‐Methoxybenzylidene)thiazolidine‐2,4‐dione derivatives have the essential pharmacophoric features of VEGFR‐2 inhibitors [ 33–38 ] (Figure 3), which include the following: the presence of a five‐membered hetero ring, thiazolidine‐2,4‐dione, substituted with 4‐methoxybenzylidene moiety, as a hydrophobic portion, forming a 5‐(4‐methoxybenzylidene)‐thiazolidine‐2,4‐dione scaffold linked to (un)substituted hydrophobic tail through ester and/or acetamide linkers containing HBA–HBD, which interacted as HBA through its C═O and as HBD through its NH with the essential amino acid residues Asp1044 and Glu883, respectively. Also, its (un)substituted hydrophobic phenyl tail occupied the hydrophobic pocket formed by Cys1043, Leu1033, Val914, Val897, and Lys866.…”

Design, synthesis, molecular docking, anticancer evaluations, and in silico pharmacokinetic studies of novel 5‐[(4‐chloro/2,4‐dichloro)benzylidene]thiazolidine‐2,4‐dione derivatives as VEGFR‐2 inhibitors

“…5‐([4‐Chloro/2,4‐dichloro]benzylidene)thiazolidine‐2,4‐dione derivatives have the essential pharmacophoric features of VEGFR‐2 inhibitors [ 35–39 ] (Figure 3), which include the presence of five‐membered hetero ring, TZD, substituted with 4‐chlorobenzylidene and/or 2,4‐dichlorobenzylidene moieties, as hydrophobic portions, forming 5‐(4‐chlorobenzylidene)thiazolidine‐2,4‐dione and 5‐(2,4‐dichlorobenzylidene)thiazolidine‐2,4‐dione scaffolds linked to substituted hydrophobic phenyl tail through acetamide linkers containing HBA‐HBD, which interacts as HBA through its C═O and as H‐bond donor through its NH with the essential amino acid residues Asp1044 and Glu883, respectively. Also, the substituted hydrophobic phenyl tails formed hydrophobic bonding interactions with the hydrophobic pocket formed by Asp1044, Cys1043, Ile1042, Hie1024, Leu1017, Val897, Leu887, Lys866, and Glu883.…”

Selected by gene co-expression network and molecular docking analyses, ENMD-2076 is highly effective in glioblastoma-bearing rats

“…Excessive VEGFR-2 activation is an important driver of tumor angiogenesis and VEGFR-2 is significantly increased on the tumor vasculature. So, it has emerged a potential approach to anticancer therapy by blocking VEGF/ VEGFR-2 signaling pathway [36]. Many small molecular drugs blocking VEGFR-2 such as ramucirumab and aflibercept have been demonstrated as prospective anticancer drugs.…”