Antimicrobial quinoline triazoles: synthesis, docking, and dynamic simulation studies against biofilm-associated...

The alarming rise of multidrug-resistant (MDR) bacterial pathogens poses a significant challenge to current antimicrobial therapy, challenging the development of novel, structurally diverse agents. In this study, a new series of phenylquinoline-triazoles (PQTs) 4a-l was rationally designed and synthesized using a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry approach. Synthesized PQTs were characterized by standard analytical techniques, including ¹H NMR, ¹³C NMR, HRMS, and spectroscopic analyses. The antimicrobial efficacy of PQTs 4a-l was evaluated against a panel of clinically relevant biofilm-causing bacterial strains, including Streptococcus pneumoniae (MTCC 1936), Staphylococcus aureus (MTCC 737), Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424), and methicillin-resistant Staphylococcus aureus (MRSA). Candida albicans was the only fungal strain utilized, considering its role in biofilm formation in several infections, including UTI (Urinary Tract Infection). In the results, three PQTs exhibited potent broad-spectrum antibacterial activity, predominantly against Gram-positive strains and MRSA. Due to the activity selectivity, a molecular docking study was executed against the penicillin-binding protein 2a (PBP2a), a key resistance factor in MRSA (PDB ID: 6H5O), and the best compounds screened were subjected to test the PBP2a inhibition potential in vitro. The most active compounds exhibited strong binding affinities and favorable interaction forms within the active site of PBP2a, including hydrogen bonding and π-π stacking with key amino acid residues. Furthermore, the docked complexes were subjected to 100 ns molecular dynamics (MD) simulations, which confirmed their structural stability and robust interactions under physiological conditions. Furthermore, in silico ADME and drug-likeness profiling suggested good pharmacokinetic properties. In conclusion, we identified compounds 4d, 4i, and 4 k as are most effective PQTs among 4a-l with remarkable antimicrobial potentials. These findings determine that PQTs are promising scaffolds for combating resistant bacterial infections such as MRSA and warrant further preclinical investigation.