Rational design and antibacterial assessment of novel pyranopyrazole derivatives: a combined experimental and in silico study

Pyranopyrazole derivatives were synthesized via multicomponent reactions and characterized using spectroscopic techniques including IR, 1H-NMR, 13C-NMR, and mass spectrometry. In vitro antibacterial evaluation revealed that compounds 2b, 3a, 5b, and 7b exhibited significant activity against Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), while compounds 4b, 4d, 6b, and 8b demonstrated potent activity against Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli). Quantum chemical calculations at the DFT/B3LYP/6-31G(d,p) level revealed HOMO–LUMO energy gaps ranging from 4.50 to 5.38 eV, with lower energy gaps correlating with enhanced antibacterial activity. Molecular electrostatic potential (MEP) analysis identified key electron-rich and electron-deficient regions responsible for target recognition. In silico molecular docking studies against tyrosyl-tRNA synthetase, an essential bacterial enzyme, demonstrated strong binding affinities with binding energies ranging from −7.84 to −11.30 kcal/mol and calculated inhibition constants (Ki) of 5.23 to 1790 nM. Key interactions involved hydrogen bonding and π-π stacking with active site residues Tyr34, His48, Asp177, and Gln196. ADME property predictions indicated favorable drug-like characteristics with compliance to Lipinski’s Rule of Five and high gastrointestinal absorption. These outstanding results could be due to the presence of aromatic moiety, halogen atom and cyano-group which enhance lipophilicity and membrane permeability in addition to the synergistic effect of both pyran and pyrazole nucleus. These integrated findings establish pyranopyrazoles as promising scaffolds for antibacterial drug development.