Molecular Dynamics and Density Functional Theory Analysis of Novel Acridine Derivatives Targeting Bacterial Topoisomerase IV

A series of nine 9‐substituted acridine derivatives was prepared by a catalyst‐free microwave‐assisted method and evaluated for antibacterial, antibiofilm, antioxidant, antihemolytic, and urease‐inhibitory activities. Compounds A2 and A3 displayed the strongest antibacterial effects against both Gram‐positive and Gram‐negative bacteria, including selected clinical and references isolates (MIC = 31.25–500 µg mL ⁻¹ ). Compound A7 exhibited the highest antibiofilm activity and the most potent urease inhibition against jack bean and Helicobacter pylori ureases (IC ₅₀  = 97.3 ± 1.89 and 156.2 ± 2.41 µg mL ⁻¹ , respectively). A5 showed the best DPPH radical‐scavenging capacity, while A1, A5, A7, and A9 produced marked antihemolytic effects. Molecular docking against Escherichia coli topoisomerase IV and xanthine oxidase, followed by a 300 ns molecular dynamics simulation of the A7–topoisomerase IV complex, provided structural hypotheses consistent with the experimental data. DFT calculations further indicated favorable electronic properties for selected derivatives. Overall, A7 emerges as a promising acridine scaffold for further structural optimization and experimental target validation.