One-step construction of tetra/tricyclic thieno[3,2-e] [1,2,4]triazolo[4,3-a]pyrimidinones as potential antitumor agents

In this work, an efficient and scalable synthetic route has been established for the assembly of structurally diverse triazolo[4,3–a]pyrimidine derivatives from readily available starting materials. Central to this approach is an NH–selective heterocyclization, which proceeds smoothly under mild reaction conditions and is governed by the thermodynamic preference for the triazolopyrimidine scaffold, as quantitatively demonstrated by calculated free energy differences. The structures of all newly synthesized compounds were unambiguously determined by ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry. Notably, single-crystal X-ray diffraction analysis of compound 6s showed unequivocal confirmation of molecular architecture and provided mechanistic insight into the cyclization process. Preliminary biological assays demonstrated that several target compounds displayed potential antiproliferative effects against HepG2 cancer cells. Computational docking analyses revealed that compounds 6l and 7j bind to EGFR in a mode highly similar to that of a known reference inhibitor, highlighting its promise as a scaffold for further medicinal chemistry optimization. These studies not only broaden the triazolopyrimidine heterocyclic system but also lay a foundation for the further design and discovery of novel anti-tumor agents.