Antibacterial Activity of Quinoline‐Based Derivatives against Methicillin‐Resistant Staphylococcus aureus and Pseudomonas aeruginosa: Design, Synthesis, DFT and Molecular Dynamic Simulations

Abstract

Bacterial virulence becomes a significant challenge for clinical treatments, particularly those characterized as Multi‐Drug‐Resistant (MDR) strains. Therefore, the preparation of new compounds with active moieties could be a successful approach for eradication of MDR strains. For this purpose, newly synthesized quinoline compounds were prepared and tested for their antimicrobial activity against Methicillin‐Resistant Staphylococcus Aureus (MRSA) and Pseudomonas Aeruginosa (PA). Among the synthesized derivatives, compounds 1‐(quinolin‐2‐ylamino)pyrrolidine‐2,5‐dione (8) and 2‐(2‐((5‐methylfuran‐2‐yl)methylene)hydrazinyl)quinoline (12) were shown to possess the highest antimicrobial activity with the minimum inhibitory concentration with the values of 5±2.2 and10±1.5 μg/mL towards Pseudomonas aeruginosa without any activity towards MRSA. Interestingly, compounds 2‐(2‐((1H‐indol‐3‐yl)methylene)hydrazinyl)quinoline (13) and 2‐(4‐bromophenyl)‐3‐(quinolin‐2‐ylamino)thiazolidin‐4‐one (16c) showed significant inhibition activity against Staphylococcus aureus MRSA and Pseudomonas aeruginosa. Compound 13 (with indole moiety) particularly displayed excellent bactericidal activity with low MIC values 20±3.3 and 10±1.5 μg/mL against Staphylococcus aureus MRSA and Pseudomonas aeruginosa, respectively. Effects molecular modelling was used to determine the mode of action for the antimicrobial effect. The stability of complexes formed by docking and target‐ligand pairing was evaluated using molecular dynamics simulations. The compounds were also tested for binding affinity to the target protein using MM‐PBSA. Density‐functional theory (DFT) calculations were also used to investigate the electrochemical properties of various compounds.