Abstract
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•A series of hybridized benzothiazole pyrimidine-based on targeting EGFR/HER2 and TS enzymes was designed and synthesized.•They were submitted to NCI for preliminarily cytotoxic screening.•The (IC50) of the most active compounds was performed using the MTT assay method.•Enzyme inhibition assay for EGFR /HER2 enzymes was examined.•Enzyme inhibition assay for TS enzyme was performed.•Molecular docking into EGFR, HER2 and TS binding sites was performed.
Multi-targeted anticancer drugs are in focus as a promising research topic. A new series of benzothiazoles hybridized with pyrimidine moiety was designed and synthesized using the lead compound 4a. Various chemical modifications on the pyrimidine ring of 4a at four different positions were done in a trial to get new multi-targeted anticancer agents. The structures of the newly synthesized compounds were established on their elemental analyses and spectral data. All final synthesized derivatives were submitted to the National Cancer Institute (NCI), USA, to be screened for their in vitro anticancer activity. Further evaluation for the cytotoxic activity of the most active compounds was performed using the MTT assay method. Compounds 4d, 8d, 8h, 8i and 17 were then selected for examining their in vitro enzyme inhibitory activities against EGFR, HER2 and TS enzymes using lapatinib and 5FU as standards. Furthermore, cell cycle analysis and apoptosis induction detection were also evaluated. Finally, molecular docking studies were carried out for compounds 4d, 8d, 8h, 8i and 17 to interpret their observed enzymatic activities based on the ligand–protein interactions.