Quinoxaline–Triazole Hybrids: Exploring the Impact of Substituent Architecture on Cytotoxic Potency and Receptor Interaction

A series of quinoxaline–1,2,4‐triazole derivatives ( 6a – 6l ) was synthesized and characterized by NMR and mass spectrometry; yields reached 80% for the long‐chain alkyl members, which points to substituent architecture as the determining factor in synthetic efficiency. MTT assays against MCF‐7, HeLa, and HepG2 cells identified 6e and 6k as the most active compounds, with IC 50 values of 50.83–62.69 µg/mL across the three lines. Docking against the adenosine A1 receptor gave binding energies of −9.02 kcal/mol for 6e and −9.24 kcal/mol for 6k , driven by hydrophobic and π–π interactions with key binding‐site residues. Ligand–receptor complexes remained stable through 600 ns of molecular dynamics, and umbrella sampling estimated binding free energies of −129.46 and −88.46 kJ/mol, respectively. ADMET predictions indicated drug‐likeness and favorable gastrointestinal absorption. 6e and 6k are therefore taken forward as lead candidates for mechanistic, pharmacological and in vivo evaluation.