Design, one-pot green synthesis, computational studies, and biological evaluation of novel pyran-pyridine hybrids for targeting MCF-7 breast cancer cell line

This study reports a catalyst-free, one-pot synthesis of novel pyran-pyridine hybrids (4a–j). The target compounds were obtained in high yields (68–83%) under mild, green conditions in acetonitrile. Structural elucidation was confirmed using comprehensive spectroscopic and analytical techniques (NMR, FTIR, MS, elemental analysis). This work establishes a novel molecular architecture by strategically conjugating the pyran and pyridine pharmacophores into a single, well-defined hybrid scaffold. The resulting compounds exhibit a unique multi-faceted biological profile, distinguished from conventional pyran or pyridine derivatives by their concurrent potent anticancer, antibacterial, and antioxidant activities. The hybrids demonstrated significant biological potential. They exhibited notable antibacterial activity against Gram-positive and Gram-negative bacteria, with compounds 4a and 4e showing the highest efficacy. Furthermore, several compounds exhibited potent and selective cytotoxic effects against the MCF-7 breast cancer cell line, with IC 50 values as low as 10.05 ± 0.011 µM, while demonstrating lower toxicity toward non-cancerous MCF-10A cells. Molecular docking studies against the C-terminal DSS1-binding domain of the BRCA2 protein (PDB ID: 3EU7) revealed strong binding affinities for the most active compounds, a finding corroborated by 100-ns molecular dynamics simulations that confirmed the stability of the ligand–receptor interactions. In silico ADMET profiling indicated promising drug-like properties for the entire series. Additionally, the compounds displayed considerable antioxidant activity in a DPPH radical scavenging assay. The integration of an efficient green synthesis with compelling multi-faceted biological activities positions these pyran-pyridine hybrids as promising scaffolds for further development in antimicrobial and anticancer drug discovery.