Novel heterocyclic-fused pyrimidine derivatives: Synthesis, molecular modeling and pharmacological screening

•Design and synthesis of novel heterocyclic-fused pyrimidines.•Antiproliferative activity of novel heterocyclic-pyrimidines against MCF7.•Evaluation of VEGFR and c-Src enzyme inhibition by heterocyclic-fused pyrimidines.•Docking of the new compounds in the active site of VEGFR and c-Src.

Novel heterocyclic-fused pyrimidines viz pyrrolo[1,2-c]pyrimidines 4–8, pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines 9–14, pyrimido[4′,5′:4,5]pyrimido[1,6-a]azepines 16–18, pyrrolo[1′,2′:1,6]pyrimido[4,5-d][1,3]thiazines 19a,b and 1,3-thiazino[4′,5′:4,5]pyrimido[1,6-a]-azepine 19c were designed and synthesized as potential anticancer agents. In this investigation all the newly synthesized compounds were subjected to cytotoxic screening against MCF-7 breast cancer cell line. Moreover, kinase inhibitory assay was done for compounds 5, 7, 9 and 18 against the non-receptor and receptor tyrosine kinases c-Src and VEGFR, respectively. The tested compounds were more potent against c-Src than VEGFR, and the highest activity was observed for 18 showing 81% c-Src activity inhibition. Finally, molecular docking was performed with c-Src and VEGFR in an attempt to simulate and understand the possible binding interactions underlying the association between these small molecules and the kinase enzyme ATP binding pocket essential amino acids.

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