Design, multicomponent synthesis, and molecular modelling studies of tetrazole biphenyls as REV-ERBα modulators.

The efficient synthesis of biphenyl tetrazole derivatives was achieved through a one-pot multicomponent reaction catalyzed by iron nanoparticles supported on silica (Fe/SiO₂). This green and sustainable approach offers significant advantages over conventional catalytic systems, including high yields (up to 92 %), mild reaction conditions (100 °C), and excellent catalyst recyclability. The methodology involves a Suzuki-Miyaura coupling reaction followed by an in situ [2 + 3] cycloaddition, with dimethylformamide (DMF) as the solvent. The use of Fe/SiO₂ minimizes hazardous waste, aligns with green chemistry principles, and reduces overall production costs. Tetrazole-containing biphenyl scaffolds, known for their pharmacological significance, were evaluated as modulators of nuclear receptor REV-ERBα (NR1D1), a key target in metabolic disorders, inflammation, and related diseases. Molecular docking studies, revealed favorable ligand-receptor stabilization, characterised by π-π stacking and hydrophobic interactions with the ligand-binding domain. In vitro dual-luciferase reporter assays using HEK293 cells confirmed agonist activity, with EC₅₀ values ranging from 3.1 to 25.3 µM, indicating measurable transcriptional repression of the Bmal1 promoter. Among the tested analogs, 3d (4'-methoxy-4-yl) and 3a (2'-ethyl-2-yl) exhibited the highest activity (EC₅₀ = 4.9 and 5.2 µM, respectively), supported by strong docking affinities (-8.2 to -10.7 kcal/mol). Collectively, these findings establish biphenyl-tetrazole derivatives as a novel class of partial REV-ERBα agonists, bridging classical sartan-like frameworks with circadian pharmacology and offering a promising scaffold for antidiabetic and metabolic disease drug discovery.