Green Synthesis, Characterization, and Biological Activity of 4-Aminoquinoline Derivatives: Exploring Antibacterial Efficacy, MRSA Inhibition, and PBP2a Docking Insights

4-Aminoquinoline derivatives were synthesized on a small scale using a novel microwave-assisted method, and scaled up in sealed tubes. The synthesis adhered to green chemistry principles, employing a solvent-free approach for both the reaction and purification. The purification was achieved through simple washing, no need for column chromatography. All reactions were conducted at temperatures between 90–150 ºC within 90–120 minutes, achieving yields of up to 95%. The products were characterized using FT-IR, 1H- and 13C-NMR spectroscopy, and HR-MS spectrometry. Antibacterial and antifungal activity testing revealed that four compounds exhibited moderate antibacterial activity. Compound 6-chlorocyclopentaquinolinamine demonstrated a strong MIC of 0.125 mM against MRSA, while compound 2-fluorocycloheptaquinolinamine showed a MIC of 0.25 mM against S. pyogenes. A Structure-Activity Relationship (SAR) docking study was conducted within the Penicillin Binding Protein (PBP) binding site. Docking analysis of anti-MRSA com-pounds 7-chlorophenylquinolinamine, 6-chlorocyclopentaquinolinamine, and 2-fluorocycloheptaquinolinamine in the MRSA PBP2a binding pocket (PDB: 4DK1) revealed that 6-chlorocyclopentaquinolinamine and 7-chlorophenylquinolinamine interacted via hydrophobic (ALA601, ILE614), hydrogen bonding (GLN521), and halogen interactions (TYR519, THR399). Compound 6-chlorocyclopentaquinolinamine exhibited superior MRSA inhibition (20 mm inhibition zone vs. 12.5 mm for 7-chlorophenylquinolinamine), attributed to additional π-alkyl interactions and favorable docking parameters, including higher Ligscore2 (4.03), PLP1 (59.15), and Dock Score (34.31). In contrast, compound 2-fluorocycloheptaquinolinamine exhibited weaker activity due to its bulky structure, limited interactions, and less favorable docking scores.