Synthesis, Biological Evaluation and Molecular Docking Studies of Newly Synthesized 4- Amino Quinazoline Derivatives as Potential Multitarget Anticancer Agents.

A series of 4-aminoquinazoline linked to cyanopyrimidine derivatives (6a-c and 7a-f) was designed, synthesized with good yields and screened at National Cancer Institute (NCI)-disease oriented anticancer screen protocol against nine panel of cancer cell lines. Comprehensively, the structures of the synthesized compounds were confirmed by different spectroscopic methods like 1H-NMR, 13C-NMR and HRMS. Moreover, the most active compound 7a was selected for invitro enzyme inhibitory activities against epidermal growth factor receptor, cyclin dependent kinase-2 and TS enzymes, it exhibited good EGFR, CDK-2 and TS inhibition activity with IC50values of 0.313 +/- 0.019, 0.485 +/- 0.025 and 32.57 +/- 1.98 mu M, respectively, in comparison to references with IC50 value of 0.03 +/- 0.002, 0.289 +/- 0.015 and 8.099 +/- 0.49 mu M, respectively. Cell cycle analysis and apoptosis were evaluated on three different cancerous cells; UO-31, MCF7 and IGROV-1. Finally, the molecular modelling for compound 7a inside the ATP binding site of epidermal growth factor receptor and cyclin dependent kinase-2 enzymes was performed to predict the binding mode to the active site of these enzymes using lapatinib and ribociclib as standards respectively. Our research found that quinazoline-containing cyanopyrimidine derivatives were promising cytotoxic agents for further study.