Synthesis and Antibacterial Evaluation of Novel Ketoprofen Derivatives as Bacterial Transpeptidase Inhibitors via Combined  In Silico  and  In Vitro  Approaches

Rawaa Fathel Abbas; Muthanna Saadi Farhan

doi:10.22146/ijc.109419

Synthesis and Antibacterial Evaluation of Novel Ketoprofen Derivatives as Bacterial Transpeptidase Inhibitors via Combined In Silico and In Vitro Approaches

https://doi.org/10.22146/ijc.109419

Rawaa Fathel Abbas^(1*), Muthanna Saadi Farhan⁽²⁾

(1) Ministry of Health and Environment, Al-Russafa Health Directorate, Al-Alwiyah Maternity Hospital, Karrada – Al-Nidhal Street, Baghdad 10089, Iraq
(2) Department of Pharmaceutical Chemistry, College of Pharmacy, University of Baghdad, Bab Al-Moudam, Baghdad 10001, Iraq
(*) Corresponding Author

Abstract

Ten ketoprofen derivatives were synthesized in two steps, producing six Schiff base derivatives from ketoprofen hydrazide and four hydrazine carbothioamide derivatives. Structural confirmation was achieved via FTIR, ¹H-, and ¹³C-NMR spectroscopy. The prepared compounds were tested for their ability to kill bacteria against two types of Gram-positive bacteria, Staphylococcus aureus and Streptococcus pyogenes, and two types of Gram-negative bacteria, Escherichia coli and Klebsiella pneumoniae, using the resazurin broth test. In silico studies were also conducted to calculate the binding energies of the synthesized compounds against a key antimicrobial target, followed by molecular dynamics simulation and ADME prediction. Molecular docking studies revealed that 2-(3-benzoylphenyl)-N'-(4-hydroxy-3,5-dimethylbenzylidene)propane hydrazide (RAF1) had the strongest binding to the 3UDI domain (ΔG = –8.19 kcal/mol), while molecular dynamics simulation confirmed the stability of the ligand–receptor complexes with acceptable RMSD and RMSF values. 2-(2-(3-benzoylphenyl)propanoyl)-N-(4-chlorophenyl)hydrazine-1-carbothioamide (RAF9) exhibited a significantly reduced minimum inhibitory concentration against S. aureus compared to penicillin G. Furthermore, 2-(3-benzoylphenyl)-N'-(4-(benzyloxy)benzylidene)propane hydrazide (RAF5) exhibits superior zone inhibition against S. pyogenes compared to penicillin G. These results suggest that ketoprofen derivatives exhibit promising activity as bacterial transpeptidase inhibitors and warrant further optimization.

Keywords

ketoprofen derivatives; transpeptidase inhibitors; molecular docking; Schiff base derivatives

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DOI: https://doi.org/10.22146/ijc.109419