Exploring the Potential of New 7‐Chloroquinoline‐benzylamine Hybrids as Antimicrobials: Synthesis, Biological Activity and MD Simulation Studies

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Abstract
Novel drug like chloroquinoline‐benzylamine hybrids were synthesized and subjected to comprehensive antibacterial evaluation in the present investigation. The pharmacological evaluation comprises determination of minimum inhibitory concentration (MIC), disk diffusion assay, hemolysis and combination assays against both Gram‐negative ( Pseudomonas aeruginosa ) and Gram‐positive ( Bacillus subtilis, Enterococcus faecalis , and Staphylococcus aureus ) bacterial strains. Among all, 7‐chloroquinoline‐benzylamine hybrid bearing p ‐bromophenyl substituent ( SA11) demonstrated significant antibacterial efficacy (MIC=128 μ g/mL) against the tested panel of Gram‐positive strains with no sign of toxicity towards human red blood cells ( h RBCs). Furthermore, another hybrid with o ‐hydroxyphenyl substitution ( SA12) exhibited notable activity against the tested isolates with MIC values ranging from 64 to 256 μ g/mL. Molecular docking studies suggested compound SA11 binds within the active site of the biofilm causing protein ( PDB: 7C7U ) further supported by the molecular dynamics (MD) simulation studies at 100 ns. Compound SA11 exhibited significant efficacy in inhibiting S. aureus growth in the disk diffusion assay. Moreover, it displayed a synergistic effect when combined with ciprofloxacin (CIP), implying its potential utility in addressing antibiotic‐resistant bacterial strains through combination therapy. The pkCSM‐Pharmacokinetics assessment indicated favourable ADME profiles for SA11 , supporting its potential as a viable drug candidate.

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