Supramolecular Networks of Picrate Derivatives with Tunable Hydrogen-bonding Densities for Selective Bacterial Killing

Abstract

To address the worldwide challenge of antimicrobial resistance by bacterial pathogens, a series of substituted anilines/acid hydrazide crystallized with picric acid (HPA) were synthesized and structurally characterized: [An+---PA-] (1), [OAP+---PA-] (2), [OMe+---PA-] (3) and [CBH+---PA-] (5) (where An: Aniline, OAP: o-aminophenol, OMe: 4-methoxyaniline, CBH: 4-chlorobenzhydrazide). X-ray crystallographic analysis shows the asymmetric unit for each compound as supramolecular 1/2-dimensional networks for 1−3 and a 3-dimensional architecture for 5, stabilized by hydrogen bonding and charge transfer. On the other hand, association of picric acid with 4-nitroaniline (NA), [(HPA)2---NA] (4), exhibit a herringbone arrangement ruled by π-π stacking. Systematic evaluation of broad-spectrum antibacterial activity against Staphylococcus aureus and Escherichia coli have established a significant structure-function correlation in their minimum inhibitory concentration (MIC) dependences, zone of inhibitions, crystal violet staining and morphological analysis. Comparative FE-SEM profiles show a prominent damage of the peptidoglycan layer in the Gram-positive cell wall while moderate blebbing in the Gram-negative outermost membranes on 24 h treatment with 5. Molecular docking proves a DNA gyrase B-inhibiting pathway for killing bacterial cells, active site being the ATP binding pocket. Docking scores indicate the most favorable protein-ligand interaction for 5 (-10.02 kcal/mol) involving Arg144, Glu58 as the key residues. All results converge to 4-chlorobenzhydrazinium picrate (5) as a lead compound for antibacterial drug development (MIC = 1 µg/mL) with a 200-fold selectivity index to S. aureus-mediated infections. This is attributed to higher hydrogen-bond density in the supramolecular network of 5 aided by acyl oxygen.