Novel pyrimidine-piperazine hybrids as potential antimicrobial agents: in-vitro antimicrobial and in-silico studies

Abstract

A series of new pyrimidine-piperazine hybrid molecules ware designed and synthesized as possible antimicrobial agents. The synthesized compounds (20 derivatives) were characterized using 1HNMR, 13C NMR, MS and elemental analysis and then the activity of the new compounds were compared with that of antibiotics.Various pathogenic bacteria including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli, as well as standard antibiotics such as ampicillin/tetracycline, ceftazidime, and vancomycin, as recommended by the clinical and laboratory standards institute (CLSI). Compounds N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl) phenyl) cyclobutanecarboxamide (9 g), 1-cyclopropyl-3-(4-(4-(5-fluoropyrimidin-2-yl) piperazin-1-yl) phenyl) urea (7c) and 1-cyclobutyl-3-(4-(4-(5-fluoropyrimidin-2-yl) piperazin-1-yl) phenyl) urea (7d) exhibited strong antimicrobial activity against K. pneumonia, with an IC50 of 27.1, 32.4, and 32.4 μg/ml, respectively. 1-cyclohexyl-3-(4-(4-(5-fluoropyrimidin-2-yl) piperazin-1-yl) phenyl) urea (7 h) and 1-ethyl-3-(4-(4-(5-fluoropyrimidin-2-yl) piperazin-1-yl) phenyl) urea (7i) showed potent antimicrobial activity against E. faecium, with an IC50 of 26.2 and 34.2 μg/ml, respectively. Notably, 1-(4-(4-(5-fluoropyrimidin-2-yl) piperazin-1-yl) phenyl)-3-phenylurea (7f) displayed excellent antimicrobial activity against P. aeruginosa, with an IC50 of 9.8 μg/mL. Moreover, molecular docking studies were carried out to determine the binding affinity and ligand interactions of the compounds with the penicillin-binding protein3. The pharmacokinetic properties (ADME) of the synthesized compounds were predicted, and a high percentage of human oral absorption was found for most of the compounds. Lipinski's rule was adhered by the majority of the compounds. Furthermore, the most potent antibacterial hit compounds, N-(4-(4-(5-fluoropyrimidin-2-yl) piperazin-1-yl) phenyl)-2-naphthamide (9e) and 1-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-3-phenylurea (7f) were selected for MD simulation studies using the Desmond (2022–4) module of Schrodinger software.