Hydrazone–Schiff Base Derivatives Bearing a Polyhydroquinoline Scaffold as Potent Antimicrobial Agents: <i>In Vitro</i>, Molecular Docking and DFT Insights

The growth of multidrug-resistant bacterial strains requires the development of new antibacterial agents with greater efficiency. This work focuses on the evaluation of hydrazone–Schiff base derivatives of polyhydroquinoline (PHQ) against antibacterial activity. The synthetic compounds have been evaluated against Klebsiella pneumoniae and Staphylococcus aureus. Compounds (14, 7, 8, 9 and 23) attributed a significant zone (19–20 mm at 2 [Formula: see text]g/mL) by comparing with the standard amoxicillin (30–32 mm), while compound (11) displayed limited effectiveness. The molecular docking analysis confirmed robust binding affinities of the compounds with the active sites of the oxidoreductase enzyme, explaining their possible mechanism of action. In addition, the density functional theory (DFT) study discovered that the electron-withdrawing substituents, including bromo and fluoro in compound (7), improve the reactivity by stabilizing negative charges in chemical reactions. In comparison, amoxicillin’s superior potency is attributed to its unique structural features that enable robust interactions with bacterial targets, a mechanism that is not solely dependent on electronic properties. This analysis underscores the importance of a multifaceted approach in drug design, considering both electronic attributes and specific target interactions for developing effective antibacterial agents.