Pyridine‐derived VEGFR‐2 inhibitors: Rational design, synthesis, anticancer evaluations, in silico ADMET profile, and molecular docking

Abstract

Novel pyridine‐derived compounds (5–19) were designed and synthesized, and their anticancer activities were evaluated against HepG2 and MCF‐7 cells, targeting the VEGFR‐2 enzyme. Compounds 10, 9, 8, and 15 were found to be the most potent derivatives against the two cancer cell lines, HepG2 and MCF‐7, respectively, with IC50 = 4.25 and 6.08 µM, 4.68 and 11.06 µM, 4.34 and 10.29 µM, and 6.37 and 12.83 µM. Compound 10 displayed higher activity against HepG2 cells than sorafenib (IC50 = 9.18 and 5.47 µM, respectively) and doxorubicin (IC50 = 7.94 and 8.07 µM, respectively). It also showed higher activity than doxorubicin against MCF‐7 cells, but lower activity than sorafenib. Compounds 9, 8, and 15 displayed higher activities than sorafenib and doxorubicin against HepG2 cells but exhibited lower activities against MCF‐7 cells. Compound 10 potently inhibited VEGFR‐2 at an IC50 value of 0.12 µM, which is nearly equipotent to sorafenib (IC50 = 0.10 µM). Compounds 8 and 9 exhibited very good activity with the same IC50 value of 0.13 µM. The six most potent derivatives, 6, 9, 8, 10, 15, and 18, were tested for their cytotoxicity against normal Vero cells. Compounds 6, 8, 9, 10, 15, and 18 are, respectively, 1.13, 3.74, 4.18, 3.64, 2.81, and 2.00 times more toxic to HepG2 and 2.06, 1.58, 1.76, 2.54, 1.40, and 2.69 times more toxic to MCF‐7 breast cancer cells than in normal Vero cells.

Design, synthesis, in silico ADMET, docking, and antiproliferative evaluations of [1,2,4]triazolo[4,3‐c]quinazolines as classical DNA intercalators

“…Anastrozole containing a 1,2, 4-triazole ring is used in the treatment of postmenopausal women with estrogen-responsive breast cancer. [24] On the basis of the earlier findings and in continuation of our previous research in anticancer agents, [25][26][27][28][29][30][31][32][33][34][35] especially DNA intercalators, [36][37][38][39] we reported herein DNA-binding and docking studies of a new series of [1,2,4]triazolo [4,3-c]quinazoline derivatives as anticancer agents.…”

“…On the basis of the earlier findings and in continuation of our previous research in anticancer agents, [ 25–35 ] especially DNA intercalators, [ 36–39 ] we reported herein DNA‐binding and docking studies of a new series of [1,2,4]triazolo[4,3‐ c ]quinazoline derivatives as anticancer agents.…”

Design, Molecular Docking, Synthesis, Anticancer and Anti-Hyperglycemic Assessments of Thiazolidine-2,4-diones Bearing Sulfonylthiourea Moieties as Potent VEGFR-2 Inhibitors and PPARγ Agonists

“…In addition, our compounds were assessed for their VEGFR-2 inhibitory effects by applying an anti-phosphotyrosine antibody with the Alpha Screen system (PerkinElmer, Waltham, MA, USA) [67,68]. The results are described as IC 50 (50% inhibition concentration value) in Table 3.…”

Methylene Components Exchange in the Reaction of Cyanoacetohydrazide with 2-Amino-4-arylbuta-1,3-diene-1,1,3-tricarbonitriles

“…Such compounds are of interest as starting materials for the preparation of polyazaheterocycles with a bridging nitrogen atom, namely fused 1,2,4-triazines 5 [7,8], 1,2,4,3-triazaphospholo [1,5-a]pyridines 6 [9], [1,2,4]triazolo [1,5-a]pyridines 7 [10][11][12], pyrido [1,2-b] [1,2,4]triazepines 8 [13][14][15][16], and nicotinonitrile derivatives 9 [3] (Scheme 1). Compounds 4 are also promising lowmolecular-weight ligands with an antitumor effect for binding VEGFR-2 kinase [17], phosphodiesterase PDE4 [18], new antibacterial and fungicidal drugs [19], etc. In addition, 1,6-diaminopyridines 4 are used to obtain materials for nonlinear optics [8], azaheterocycles with anticancer action [11,[20][21][22], as well as PGE 2 inhibitors with anti-inflammatory activity [23].…”