New Pyrazole-Clubbed Pyrimidine or Pyrazoline Hybrids as Anti-Methicillin-Resistant Staphylococcus aureus Agents: Design, Synthesis, In Vitro and In Vivo Evaluation, and Molecular Modeling Simulation

Abstract

Two hybrid series of pyrazole-clubbed pyrimidines 5a−c and pyrazole-clubbed pyrazoline compounds 6a,b and 7 were designed as attractive scaffolds to be investigated in vitro and in vivo for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. From the results of the in vitro antibacterial screening, compound 5c showed excellent activity (minimal inhibitory concentration, MIC = 521 μM) when compared with that of the reference antibiotic levofloxacin (MIC = 346 μM). The inhibition of the target dihydrofolate reductase (DHFR) enzyme by compounds 4 and 5a−c (IC 50 = 5.00 ± 0.23, 4.20 ± 0.20, 4.10 ± 0.19, and 4.00 ± 0.18 μM, respectively) was found to be better than the reference drug trimethoprim (IC 50 = 5.54 ± 0.28 μM). Molecular modeling simulation results have justified the order of activity of all the newly synthesized compounds as DHFR enzyme inhibitors, and compound 5c exhibited the best binding profile (−13.6169386 kcal/mol). Hence, the most potent inhibitor of the DHFR enzyme, 5c, was chosen to be evaluated in vivo for its activity in treating MRSA-induced keratitis in rats and that, in turn, significantly (P < 0.0001) reduced infection in rats when compared to MRSA-treated group results.

Redirecting pantoprazole as a metallo-beta-lactamase inhibitor in carbapenem-resistant Klebsiella pneumoniae

“…Molecular modeling simulation is traditionally carried out to explore the interactions of ligands with their respective binding sites in the crystal structures of the enzymes ( Mansour et al, 2023 ) Figure 5 (upper panel) shows that the docking results of pantoprazole against the crystal structure of the New Delhi metallo β-lactamase receptor displayed a unique type of halogen bonds ( El-Abd et al, 2022 ) between the backbone of the conserved amino acid Asn220 and one of the fluorine atoms in the terminal difluoromethoxy moiety at position 5 of the benzimidazole scaffold. In addition, an arene–H-bond constructed between the non-classical Lewis base pyridine ring and the conserved amino acid Ala215 and the conspicuous hydrophobic/hydrophilic interactions expressed by cyan-shaded amino acids from the receptor side and the blue-shaded moieties from the ligand side improved the overall recognition and enhanced the ligand/receptor complex stability to score free-binding energy of −10.3401031 kcal/mol.…”