Piperazine-based Semicarbazone Derivatives as Potent Urease Inhibitors: Design, Synthesis, and Bioactivity Screening

Background: An enzyme called urease assists highly pathogenic bacteria in colonizing and maintaining themselves. Accordingly, inhibiting urease enzymes has been shown to be a promising strategy for preventing ureolytic bacterial infections. Objective: This study aimed to synthesize and evaluate the bioactivity of a series of semicarbazone derivatives. Methods: A series of piperazine-based semicarbazone derivatives 5a-o were synthesized and isolated, and their structures were elucidated by¹H-NMR and¹³C-NMR spectroscopic techniques besides MS and elemental analysis. The urease inhibition activity of these compounds was evaluated using the standard urease enzyme inhibition kit. An MTT assay was performed on two different cell lines (NIH-3T3 and MCF-7) to investigate the cytotoxicity profile. Results: All semicarbazone 5a-o exhibited higher urease inhibition activity (3.95-6.62 µM) than the reference standards thiourea and hydroxyurea (IC₅₀: 22 and 100 µM, respectively). Derivatives 5m and 5o exhibited the best activity with the IC₅₀ values of 3.95 and 4.05 µM, respectively. Investigating the cytotoxicity profile of the target compound showed that all compounds 5a-o have IC₅₀ values higher than 50 µM for both tested cell lines. Conclusion: The results showed that semicarbazone derivatives could be highly effective as urease inhibitors.