Pyrazolo-imidazolidinones: Synthesis, antimicrobial assessment and molecular modelling studies by molecular mechanic and quantum mechanic approach

Abstract

Antimicrobial resistance (AMR) and multidrug resistance (MDR) have become global therapeutic barriers and due to this, there is increasing global mortality. To overcome antimicrobial resistance, we developed a novel set of fifteen pyrazole-imidazolidinone hybrids. The synthesized compounds were characterized, and structures confirmed by spectral techniques like IR, NMR spectra and Mass data. Compounds (4a-o) were evaluated for their in vitro antimicrobial activity against Gram-positive, Gram-negative bacterial strains, as well as fungal strains by using the Mueller Hinton Broth dilution method. The results demonstrated that the compounds 4f with MIC (Minimum Inhibitory Concentration) 12.5 μg/mL against A. clavatus and 4l with MIC 12.5 μg/mL against P. aeruginosa were the most active compared to the standard drugs. The biological activity revealed that the electron-withdrawing group (4l) is responsible for the antibacterial activity whereas the electron-donating group (4b, 4d, 4e, 4f, and 4g) is accountable for the antifungal activity. The in-silico results prove the affinity of 4f, and 4l for bacterial and fungal targets. Compounds, 4a, 4b, and 4c have residues in their cavities that are comparable and have excellent affinity for such bacterial target. Further, 100 ns molecular dynamics simulations were used to evaluate the promising compound 4f interactions and stability on the fungal target 14α–demethylase enzyme. Optimization parameters, MESP (Molecular Electrostatic Potential) analysis, HUMO (Highest Occupied Molecular Orbital), and LUMO (Lowest Unoccupied Molecular Orbital) quantum parameters of the most active compound 4f were also calculated by using DFT/B3LYP theory and the 6–31 G ** base set, and the results were correlated with the anti-microbial activity.