Microwave-Assisted One-Pot Synthesis and Biological Evaluation of [1,2,3]Triazolo[1',5':1,5]pyrrolo[3,4-d]pyrimidines

Objective: This study focuses on the design, synthesis, characterization, and biological evaluation (in vitro and in silico) of novel [1,2,3]triazolo[1',5':1,5]pyrrolo[3,4-d]pyrimidines (Va–Vo) synthesized via a one-pot method. The compounds were evaluated for their anticancer activity and EGFR inhibitory effects. Methods: The synthesis of fused 1,2,3-triazoles was performed under microwave conditions using PEG-400 as the solvent. All synthesized compounds were assessed for their anticancer activity against MCF-7 and A-549 cancer cell lines. The most potent compounds were further analyzed using an EGFR enzymatic assay and in silico molecular docking studies. Results and Discussion: ESI-MS, 1H, and 13C NMR spectroscopy confirmed the identity of the new derivatives. Compounds (Vk–Vm) exhibited potent activity against MCF-7 cells, with IC50 values of 6.41 ± 0.33, 4.25 ± 0.29, and 5.65 ± 0.31 μM, respectively, compared to the standard 5-FU. Further evaluation of EGFR inhibitory activity showed that compound Vk displayed significant activity. All potent compounds exhibited higher binding energies compared to the standard erlotinib. Conclusions: A series of fused [1,2,3]triazolo[1',5':1,5]pyrrolo[3,4-d]pyrimidines were successfully synthesized and evaluated for in vitro anticancer activity. Some compounds demonstrated notable effectiveness against the MCF-7 cell line. Moreover, the potent compounds exhibited limited toxicity against normal HEK293 cells. All active compounds showed significant binding energies, ranging from –7.76 to –8.65 kcal/mol, compared to the standard erlotinib (–7.69 kcal/mol). Modifications to the potent compound Vk could lead to a promising therapeutic candidate for cancer treatment.