Design, synthesis, molecular docking, and anticancer activity of benzoxazole derivatives as VEGFR‐2 inhibitors

Abstract

Novel series of benzoxazoles 4a‐f‐16 were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT‐116, and MCF‐7 cells. HCT‐116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 5e was found to be the most potent against HepG2, HCT‐116, and MCF‐7 with IC50 = 4.13 ± 0.2, 6.93 ± 0.3, and 8.67 ± 0.5 µM, respectively. Compounds 5c, 5f, 6b, 5d, and 6c showed the highest anticancer activities against HepG2 cells with IC50 of 5.93 ± 0.2, 6.58 ± 0.4, 8.10 ± 0.7, 8.75 ± 0.7, and 9.95 ± 0.9 µM, respectively; HCT‐116 cells with IC50 of 7.14 ± 0.4, 9.10 ± 0.8, 7.91 ± 0.6, 9.52 ± 0.5, and 12.48 ± 1.1 µM, respectively; and MCF‐7 cells with IC50 of 8.93 ± 0.6, 10.11 ± 0.9, 12.31 ± 1.0, 9.95 ± 0.8, and 15.70 ± 1.4 µM, respectively, compared with sorafenib as a reference drug with IC50 of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 5c‐f and 6b,c were further evaluated for their vascular endothelial growth factor receptor‐2 (VEGFR‐2) inhibition. Compounds 5e and 5c potently inhibited VEGFR‐2 at lower IC50 values of 0.07 ± 0.01 and 0.08 ± 0.01 µM, respectively, compared with sorafenib (IC50 = 0.1 ± 0.02 µM). Compound 5f potently inhibited VEGFR‐2 at low IC50 value (0.10 ± 0.02 µM) equipotent to sorafenib. Our design was based on the essential pharmacophoric features of the VEGFR‐2 inhibitor sorafenib. Molecular docking was performed for all compounds to assess their binding pattern and affinity toward the VEGFR‐2 active site.

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, eco-friendly synthesis, molecular modeling and anticancer evaluation of thiazol-5(4H)-ones as potential tubulin polymerization inhibitors targeting the colchicine binding site

“…In continuation for our previous work of design and synthesis of new anticancer agents, [35][36][37][38][39][40][41][42][43][44][45] the main target of this work was the synthesis of new thiazol-5(4H)-ones having the same essential pharmacophoric features of the reported CBSIs (Fig. 5).…”

Anticancer activity of benzoxazole derivative (2015 onwards): a review

“…Therefore, inhibition of VEGF and VEGFR-2 signaling pathways plays a very important therapeutic target for tumor angiogenesis and subsequent tumor growth. Sorafenib is already approved as antiangiogenic drug [49,50], and based on the structure, it was found out that major VEGFR-2 inhibitory compound has 4 main features, and 3 series of compounds with benzoxazole/benzothiazole backbone were synthesized [51] (Fig. 27), and cytotoxicity was checked against various cancer cell lines HepG2, HCT-116, and MCF-7.…”