Synthesis of novel disubstituted tetrazole scaffolds via the Ugi TMS-N3 reaction and their antimicrobial evaluation molecular docking and ADME profiling

Abstract

The design and synthesis of ten disubstituted tetrazole derivatives (5a–5j) via a one-pot, four-component Ugi-azide reaction (UGI-4CR) employing 2-(4-chloro-2-formylphenoxy)acetonitrile, variously substituted primary aromatic amines, trimethylsilyl azide, and tert-butyl isocyanide in anhydrous methanol at ambient temperature, affording target compounds in excellent yields (84–88%). All compounds were unambiguously characterized by FTIR, ¹H NMR, ¹³C NMR, and ESI-MS analyses. In vitro antimicrobial evaluation revealed compound 5c (2-fluorophenyl) as the most potent antibacterial agent (MIC: 20–800 µg/mL), while the series exhibited limited antifungal efficacy. Molecular docking against penicillin binding protein 2a (PDB ID: 3ZG5) demonstrated strong binding affinities (ΔG = − 7.1 to − 7.9 kcal/mol), with compound 5f exhibiting the highest affinity (− 7.9 kcal/mol), surpassing reference gentamicin (− 6.6 kcal/mol). In silico ADME profiling confirmed high intestinal absorption (90.9–100%), favourable oral bioavailability, low CNS penetration, and moderate metabolic liability. Collectively, these findings establish the α-aminotetrazole scaffold as a promising antibacterial pharmacophore warranting further medicinal chemistry optimization.