A facile one-pot synthesis of new pyrimido[1,6-a]thieno[2,3-d]pyrimidin-4-ones 3a,b is reported via base-catalyzed reaction of 2-amino-3-cyanothiophenes 1a,b with 2,4-dichloro-5-bromo-6-methylpyrimidine 2. Subsequent treatment of the products with several amines under a mild condition gave a host of the new amino derivatives 4a-l. The target compounds were evaluated for anti-proliferative activity by a MTT assay on human breast cancer (MCF-7) and mouse fibroblast non-malignant (L929) cell lines. The activation was structural, concentration and time dependent. Doses inducing 50% cell-growth inhibition (IC50) for compounds 3a,b and 4a-l against MCF-7 cells were explored. Compounds 4f and 4l as the two most potent analogs induced a sub-G1 peak in the flow-cytometry histogram of treated cells, compared to control, indicating that apoptotic cell death is involved in compounds 4f and 4l induced toxicity. Compounds 4f and 4l exerted cytotoxic and proapototic effects on MCF-7 cell line.

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