Phthalazine‐based VEGFR‐2 inhibitors: Rationale, design, synthesis, in silico, ADMET profile, docking, and anticancer evaluations

Abstract

In the designed compounds, a new linker was inserted in the form of fragments with verified VEGFR‐2 inhibitory potential, including an α,β‐unsaturated ketonic fragment, pyrazole, and pyrimidine. Also, new distal hydrophobic moieties were attached to these linkers that are expected to increase the hydrophobic interaction with VEGFR‐2 and, consequently, the affinity. These structural optimizations have led us to identify the novel dihydropyrazole derivative 6e as a promising hit molecule. All the new derivatives were evaluated to assess their anticancer activity against three human cancer cell lines, including HepG2, HCT‐116, and MCF‐7. The results of the in vitro anticancer evaluation study revealed the moderate to excellent cytotoxicity of 6c, 6e, 6g, and 7b, with IC50 values in the low micromolar range. The inhibitory activity of VEGFR‐2 was investigated for 16 of the designed compounds. The enzyme assay results of the new compounds were compared with those of sorafenib as a reference VEGFR‐2 inhibitor. The obtained results demonstrated that our derivatives are potent VEGFR‐2 inhibitors. The most potent derivatives 6c, 6e, 6g, and 7b showed IC50 values in the range of 0.11–0.22 µM. Molecular docking and pharmacokinetic studies were also conducted to rationalize the VEGFR‐2 inhibitory activity and to evaluate the ability of the most potent derivatives to be developed as good drug candidates.

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

“…The synthesis was initiated by cyclocondensation of 2-benzoylbenzoic acid 1 with hydrazine hydrate to afford the corresponding 4-phenylphthalazin-1(2H)-one 2, which underwent chlorination by reaction with phosphorous oxychloride to afford 1-chloro-4-phenylphthalazine 3 following the reported procedures. [20,52] The chloro derivative 3 was heated under reflux with the methyl 4-aminobenzoate to afford the corresponding methyl ester derivative 4. On the contrary, the ester derivative 4 was heated under reflux with hydrazine hydrate to yield the corresponding hydrazide 5 (Scheme 1).…”

Antiproliferative evaluations of triazoloquinazolines as classical DNA intercalators: Design, synthesis, ADMET profile, and molecular docking

“…Here, we present DNA binding and docking studies of a new series of [1,2,4]triazolo[4,3‐c]quinazoline derivatives as anticancer agents, based on our earlier study in anticancer drugs, [ 8–22 ] especially DNA intercalators. [ 20,23–26 ]…”

“…Here, we present DNA binding and docking studies of a new series of [1,2,4]triazolo [4,3-c]quinazoline derivatives as anticancer agents, based on our earlier study in anticancer drugs, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] especially DNA intercalators. [20,[23][24][25][26] Intercalators interact with the DNA double helix reversibly.…”