Abstract
AIM: Antibiotic resistance is a critical global health challenge, with many pathogens developing mechanisms to evade current treatments, resulting in rising mortality from once-manageable infections. Superbugs such as methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Enterobacterales (CRE), and multidrug-resistant Pseudomonas aeruginosa are classified as urgent threats by the Centers for Disease Control and Prevention (CDC). This growing resistance underscores the urgent need for new antibacterial agents. In this study, pyrazole - pyrimidine hybrids linked to piperazine urea derivatives were explored to identify promising antibacterial scaffolds. MATERIALS AND METHODS: A series of ten pyrazole-pyrimidine-piperazine urea hybrids (U1-U10) were synthesized through a multi-step process and evaluated against six clinically relevant bacterial pathogens: Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Enterococcus faecium, and Klebsiella pneumoniae. Minimum inhibitory concentrations (MICs) were determined, and molecular docking against Serine hydroxymethyltransferase (SHMT) was performed.. RESULTS AND CONCLUSION: Several compounds displayed moderate antibacterial activity, with notable inhibition of E. faecium, including vancomycin-resistant strains. Derivatives bearing cyclopropyl (U4) and benzonitrile (U8) substituents exhibited significant activity against E. faecium and S. aureus (MIC = 100 µg/mL). Molecular docking revealed favorable binding through hydrogen bonding and hydrophobic contacts with key SHMT residues. This study identifies U4 and U8 as superior antibacterial candidates, suggesting rigid hydrophobic and electron-withdrawing substituents enhance antibacterial potency.