Anticancer evaluations of iodoquinazoline substituted with allyl and/or benzyl as dual inhibitors of EGFR WT and EGFR T790M : design, synthesis, ADMET and molecular docking.

Fifteen new iodoquinazoline derivatives, 5a,b to 18, are reported in this study and their anticancer evaluation as dual inhibitors of EGFR WT and EGFR T790M . The new derivatives were designed according to the target of structural requirements of receptors. Cytotoxicity of our compounds was evaluated against MCF-7, A549, HCT116 and HepG2 cell lines using MTT assay. Compounds 18, 17 and 14b showed the highest anticancer effects with IC 50 = 5.25, 6.46, 5.68 and 5.24 μM, 5.55, 6.85, 5.40 and 5.11 μM and 5.86, 7.03, 6.15 and 5.77 μM against HepG2, MCF-7, HCT116 and A549 cell lines, respectively. The eight highly effective compounds 10, 13, 14a, 14b, 15, 16, 17 and 18 were inspected against VERO normal cell lines to evaluate their cytotoxicity. Our conclusion was that compounds 10, 13, 14a, 14b, 15, 16, 17 and 18 possessed low toxicity against VERO normal cells with IC 50 increasing from 43.44 to 52.11 μM. All compounds were additionally assessed for their EGFR WT and EGFR T790M inhibitory activities. Additionally, their ability to bind with EGFR WT and EGFR receptors was confirmed by molecular docking. Compound 17 exhibited the same inhibitory activity as erlotinib. Compounds 10, 13, 14b, 16 and 18 excellently inhibited VEGFR-2 activity with IC 50 ranging from 0.17 to 0.50 μM. Moreover, compounds 18, 17, 14b and 16 remarkably inhibited EGFR T790M activity with IC 50 = 0.25, 0.30, 0.36 and 0.40 μM respectively. As planned, compounds 18, 17 and 14b showed excellent dual EGFR WT /EGFR T790M inhibitory activities. Finally, our compounds 18, 17 and 14b displayed good in silico ADMET calculated profiles.