Unlocking the Biological Potential of 2-Pyridones: Synthesis, Antioxidant and Antimicrobial Activity of N-Phenacylated 5/6-Chloro-2-pyridones

Aim: A simple and efficient synthesis of 14 new (9a-9n) N-phenacyl-2-pyridones with good yields (up to 75%), is reported. The synthesized derivatives were screened for their in vitro radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH), their in vitro antimicrobial potential was tested against human pathogenic bacterial strains, including Bacillus cereus, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, as well as the fungal strain Candida albicans. Method: All compounds displayed modest antioxidant activity, with compound 9b being the most potent in the DPPH radical scavenging assay. Most of the synthesized compounds exhibited good to excellent antimicrobial activity, however, the compounds (9d, and 9b) showed maximum inhibition zone diameters of 18.75, and 18.25mm respectively, demonstrating better antimicrobial potential than the standard drug streptomycin against Staphylococcus aureus. Result: However, the compound 9f was found most effective against Pseudomonas aeruginosa with a 23.25 mm zone of inhibition against a 17.50 mm zone of inhibition of the standard, streptomycin. Molecular docking of the compounds 9d and 9f with tyrosyl-tRNA synthetase revealed good binding with the target. Conclusion: The electron-withdrawing substituents on the aryl ring of synthesized N-phenacyl-2- pyridones improved the antioxidant activity, however, for Gram-positive bacteria, less lipophilic or more hydrophilic substituents, such as halogens, displayed better antimicrobial activity. Similarly, it was the more lipophilic substitutions on the aryl ring that improved the antimicrobial activity against Gram-negative bacteria.