Synthesis, DFT calculations, and molecular docking of phthalimide-triazole based p-tert -butylcalix[4]arene derivative and its analogue with antimicrobial, antiquorum-sensing, and antibiofilm properties

Abstract

Antimicrobial resistance is on the rise, constituting a public health problem which accounts for millions of global deaths annually. Thus, there is an urgent need for new antimicrobial compounds that can target virulence factors of pathogens. Supramolecules and macromolecules are attractive antimicrobial candidates since they exhibit antibiotic effects sustained for longer periods. This study reports the synthesis of a phthalimide-triazole-based p - tert -butylcalix[4]arene compound ( AT-2b ) and its analogue from p - tert -butyl phenol ( AT-1b ) and their characterization using the 13 C NMR and 1 H NMR data. There was observed agreement between experimental and theoretical chemical shifts ( 13 C and 1 H NMR) determined through DFT (density functional theory) calculations. DFT was used to obtain optimized geometries and molecular electrostatic potentials of the compounds, indicating their nucleophilic and electrophilic reactive sites. The compounds exhibited good antimicrobial activity against Pseudomonas aeruginosa, Escherichia coli , Chromobacterium violaceum, Staphylococcus aureus , and Candida albicans with MIC (minimal inhibitory concentration) values ranging from 4.88 to 312 µg/mL. The compounds inhibited violacein production against C. violaceum CV12472 as well as quorum-sensing (QS) against C. violaceum CV026, at MIC and sub-MIC concentrations, suggesting that they can disrupt intercellular signaling in bacteria. Both compounds showed concentration-dependent inhibition of swimming and swarming motilities against flagellated P. aeruginosa PA01, indicating their bacteriostatic potential. The compounds reduced biofilm formation against C. albicans, E. coli , and S. aureus , with S. aureus biofilms being the most susceptible. Structurally, AT-1b is a subunit of AT-2b and was less active than the latter. Molecular docking predictions showed negative binding energies and adequate interactions between the compounds and the receptor proteins of the pathogens, substantiating the observed antimicrobial effects.