Design and synthesis of metronidazole-substituted dihydropyrimidinones with biological evaluation and molecular docking studies

Abstract Metronidazole is a well-known Nitroimidazole drug with comprehensive antibacterial action. In this study, a series of novel Metronidazole-substituted 3,4-dihydropyrimidinones ( 3a–3j ) were synthesized via a modified Biginelli reaction to explore their potential as antibacterial agents. The newly synthesized compounds were assessed for their effectiveness on P. aeruginosa , E. coli , S. aureus , and B. subtilis . Most of the compounds showed considerable antibacterial effects on both Gram-positive and Gram-negative strains. Of all the compounds tested, 3d exhibited the strongest antibacterial effect, with MIC values between 0.98 and 3.91 μg/mL, comparable to those of conventional antibiotics. To gain deeper insight into its mode of action, its inhibitory effect on S. aureus tyrosyl-tRNA synthetase (TyrRS) was also evaluated. 3d was the most effective at inhibiting the enzyme, with an IC 50 of 2.1 ± 0.10 μM and a favorable selectivity index (SI > 10), indicating a promising therapeutic profile. Additionally, molecular docking of 3d into the TyrRS active site revealed stable binding interactions that support its observed inhibitory activity. These outcomes reveal that the antibacterial activity of the synthesized compounds is likely mediated through TyrRS inhibition, highlighting their potential as effective antibacterial agents with a novel target.