Assessment of novel 1,2,3,4-tetrahydroquinoline-triazole hybrids compounds as inhibitors of <i>E. coli</i> DNA GyraseB: in vitro and in silico investigation

Ten novel 1,2,3,4-tetrahydroquinolone-triazole compounds (denoted as <b>6a</b>-<b>6j</b>) were synthesized using click chemistry. These compounds were thoroughly characterized using various analytical techniques, such as FT-IR, mass spectrometry,¹H NMR, and ¹³C NMR. To gather a deeper understanding regarding structural properties of the synthesized compounds, we conducted Density Functional Theory (DFT) studies employing the B3LYP/6-311G (d,p) methodology. These calculations allowed us to evaluate important properties such as the HOMO-LUMO energy gap, chemical potential (µ), electrophilicity (ω), chemical hardness (η), dipole moment (Debye), and total energy (a.u.) for the synthesized hybrids. Moving on to the practical application of these hybrids, we evaluated <i>in vitro</i> antimicrobial inhibitory potential against two gram-positive and two gram-negative strains, and three fungal strains. Obtained outcomes revealed a range of antibacterial activity, with some compounds exhibiting excellent to moderate efficacy. Compounds <b>6b</b> and <b>6i</b> showed a very good result with a MIC of 12.5 μg/mL compared to standard Ciprofloxacin (MIC 25 μg/mL), demonstrating strong antibacterial activity against <i>E. coli</i> among the <b>6a</b>-<b>6j</b> compounds. Furthermore, <i>in silico</i> docking validated our compounds’ interaction with <i>E. coli</i> DNA gyrase B. Further, a 200 ns simulation revealed that the promising compounds maintained stability within the binding cavity, with RMSD values below 3 Å, and exhibited reduced structural fluctuations compared to the Apo protein, as evidenced by lower average RMSF values in the ligand-protein complexes. Additionally, an <i>in silico</i> ADME study assessed the drug-likeness of the hybrids, offering insights for future drug development.