Novel 4-(2-arylidenehydrazineyl)thienopyrimidine derivatives as anticancer EGFR inhibitors: Design, synthesis, biological evaluation, kinome selectivity and in silico insights
Heba A. Elsebaie, Eman A. El-Bastawissy, Kamel M. Elberembally, Eman F. Khaleel, Rehab Mustafa Badi, Moataz A. Shaldam, Wagdy M. Eldehna, Haytham O. Tawfik, Tarek F. El‐Moselhy
Abstract
The current study discovered fifteen new thieno[2,3- d ]pyrimidine derivatives with potential anticancer action, including 5a-l , 6 , and 7a-b . Results from the NCI screening revealed that compounds 5f-i and 7a significantly inhibited the proliferation of MDA-MB-468 cells at mean GI% and GI 50 levels. Compared to staurosporine, these compounds ( 5f-i and 7a ) demonstrated better safety towards typical WI-38 cells. Compounds 5g and 7a demonstrated the highest inhibition (two-digit nanomolar) when compared to erlotinib when their potency was tested on EGFR kinase. Considering the outcomes above, 5g was examined for its ability to disrupt the cell cycle with trigger apoptosis in breast cancer MDA-MB-468 cell lines. The apoptosis markers Bax, Bcl-2, Caspase-8, and Caspase-9, were detected. In silico molecular docking and dynamic simulation were used to explain the biological activities of the most potent compound.