Design, Synthesis and Molecular Docking of New Thieno[2,3‑d]Pyrimidin-4-One Derivatives as Dual EGFR and FGFR Inhibitors

Abstract

Novel thienopyrimidinone hybrids 5–25 were developed and synthesized as potential inhibitors of human EGFR and FGFR. The in vitro antiproliferative action of all compounds, towards the human breast tumor cells MDA-MB-231 and MCF-7, was evaluated with doxorubicin serving as a reference (IC₅₀ = 6.72 µM). Compound 23 demonstrated the highest anti-breast cancer efficacy against both cellular lines having IC₅₀ ranging from 2.95 to 3.80 µM. The enzyme inhibition of human EGFR and FGFR by the most active candidates 18, 21and 23–25 was further evaluated. Compounds 21 and 25 were the best EGFR inhibitors having IC₅₀ values of 0.077 and 0.059 µM, respectively, in comparison to Erlotinib (IC₅₀ = 0.04 µM). In comparison with Staurosporine (IC₅₀ = 0.024 µM), compounds 24 and 25 were the most active FGFR inhibitors having IC₅₀ values of 0.055 and 0.029 µM, respectively. The study of molecular docking was carried out among the most active EGFR inhibitors 21 and 25 and the most active FGFR inhibitors 24 and 25 to examine the relation between the binding pattern of these compounds with EGFR and FGFR catalytic active sites and their biological activity, whereas the computational results were aligned with the biological results. Finally, compound 25, which was found to be the best dual inhibitor against EGFR and FGFR, was tested for inducing apoptosis and affecting cellular arrest within G2/M phase as well as it was screened to measure its safety towards normal breast cells MCF10a with IC₅₀ value of 47.16 µM in contrast to the reference Staurosporine (IC₅₀ = 18.86 µM). Accordingly, compound 25 could be considered as a potential breast cancer therapy.