We report the design, synthetic route, and cytotoxicity of a library of 49 newly synthesized tricyclic oxazolo[5,4‐d]pyrimidines. The condensed pyrimidinones were constructed from ethyl 5‐aminooxazole‐4‐carboxylate building blocks. A tricyclic ring system was built using the naturally occurring mackinazolinone alkaloid with a focus on the molecular diversity at position C‐2 of the oxazole ring. Synthesized compounds were evaluated against a panel of human cancer cell lines including MCF‐7 (breast), HeLa (cervical), and A549 (lung) in vitro. The results revealed that substitution of halogen‐related aromatic fragments at position C‐2 of the oxazole ring may serve as promising anticancer drug candidates.

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The chemical transformation of the tricyclic furo[2,3‐d]pyrimidines was performed under isosteric and scaffold‐hopping strategies focusing on the synthesis of its arylidene and imine‐containing derivatives. Naturally‐occurring alkaloids mackinazolinone and isaindigotone were as templates of target heterocycles. Synthesized compounds evaluated for their antitumor activity on human cancer cervical HeLa, breast MCF‐7, and colon HT‐29 cell lines. Four compounds: 8c, 8e, 10b, and 10c demonstrated potency against HeLa and HT‐29 cell lines, and IC50 values were between 7.37–13.72 μM, respectively. The molecular docking results showed that compounds 8c and 10b had good binding and high matching with the target EGFR protein.