New quinoxaline-based VEGFR-2 inhibitors: design, synthesis, and antiproliferative evaluation with in silico docking, ADMET, toxicity, and DFT studies

Figures

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  Fig. 1. Chemical structures of some FDA-approved VEGFR-2 inhibitors.

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  Fig. 2. Rational design of the new proposed VEGFR-2 inhibitors.

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  Scheme 1. General synthetic route of target salts 5 and 6; reaction conditions: (i) glacial acetic acid/H2O/reflux/2 h, (ii) thiourea/EtOH/reflux/6 h, (iii) Alc. KOH/reflux/30 min.

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  Scheme 2. : General synthetic route of target intermediates 10a–d and 14; reaction conditions: (i) ClCH2COCl/NaHCO3/DMF/r.t./1 h, (ii) SOCl2/DMF/DCE/reflux/4 h, (iii) RNH2/TEA/CH3CN/r.t./8 h, (iv) CH3OH/conc. H2SO4/reflux/8 h, (v) NH2NH2·H2O/ethanol/reflux/8 h, (vi) 13/TEA/CH3CN/r.t./8 h.

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  Scheme 3. General synthetic route of target final compounds 15a–d and 16; reaction conditions: (i) 10a–d/cat. KI/DMF/WB/6 h, (ii) 14/cat. KI/DMF/WB/6 h.

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  Scheme 4. General synthetic route of target final compounds 17a–d and 18; reaction conditions: (i) 10a–d/cat. KI/DMF/WB/6 h, (ii) 14/cat. KI/DMF/WB/6 h.

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  Fig. 3. Cycle phases after the treatment with compound 17b, **p < 0.01.

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  Fig. 4. The immunoblotting of the apoptotic markers (normalized to β-actin). *p < 0.05, **p < 0.01, ***p < 0.001.

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  Fig. 5. Validation of the docking process.

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  Fig. 6. Interaction of sorafenib with the essential amino acids inside VEGFR-2 active site.

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  Fig. 7. 3D representation of 15b with VEGFR-2.

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  Fig. 8. 3D representation of 17b with VEGFR-2.