N-arylacetamide-functionalized chitosan derivatives: Synthesis, structural characterization, antibacterial activity...

Novel N-Arylacetamide-functionalized chitosan derivatives were synthesized and characterized by FT-IR spectroscopy, ¹H NMR and XRD analysis methods. The antibacterial was analyzed by the minimum inhibitory concentration (MIC) method of new derivatives obtained from modified chitosan against different Gram-positive and Gram-negative strains. In particular, the synthesized chitosan N-arylacetamide derivatives showed an identical high activity in all tests (62.5 μg/mL MIC vs. unmodified chitosan and commercial antibiotics). Molecular docking and MM-GB/SA calculations showed that the top scoring-compound, CS-PPHA had a docking score of -15.38 kcal/mol and ΔGbind (MM-GB/SA) of -117.02 kcal/mol. Results of molecular dynamics simulations provided additional indication that CS-PHA, CS-MPHA, CS-DMPHA and CS-NPHA maintain a rigid and stable binding mode with low backbone deviations (RMSD ≤ 1.59 Å). By contrast, the CS-OPHA and CS-PPHA derivatives all trigger pronounced global conformational rearrangements (RMSD ≥ 2.07 Å). These quaternary transitions at the macroscopic scale are not related to core unfolding events but rather can be attributed to a quite strong and spatially compact hyper-flexibility from within a gating loop (residues 190-205). In particular, in the presence of CS-OPHA, this loop displays a pronounced fluctuation peak at nearly 7.0 Å that allows room for the protein to take up the bound ligand. These results highlight the potential of N-arylacetamide-containing chitosan derivatives as effective antibacterial agents for biomedical and surface-coating applications.