Exploring New Thiosemicarbazide Derivatives Bearing Imidazolidine Ring as Potential Antimicrobial Agents: Design, Synthesis, and Molecular Dynamics Studies

Extracellular exo-β-(1,3)-glucanase is among the cell-wall enzymes that play important roles in cell-wall synthesis. Many antimicrobial agents act by targeting those specific enzymes to inhibit bacterial or fungal cell wall formation. In this context, we aimed to synthesize a novel series of N-substituted-2-[3-(methylsulfonyl)-2-oxoimidazolidine-1-carbonyl]hydrazine-1-carbothioamide derivatives (1-16). The structures of the synthesized compounds (1-16) were elucidated by using spectroscopic methods such as IR, ¹H NMR, ¹³C NMR, ¹³C APT NMR, and 2D NMR, as well as elemental analysis data. All thiosemicarbazide compounds (1-16) were screened for antimicrobial activity against seven bacteria (Staphylococcus aureus, MRSA, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterococcus faecalis) and three fungi (Candida albicans, Candida tropicalis, and Candida parapsilosis) strains. Among the compounds, 3 and 14 demonstrated the highest antibacterial activities against S. aureus with the MIC values in the range of 156.24-312.5 µg/mL. On the other hand, compound 9 showed the strongest antifungal activity in the series against all three fungi strains, with the MIC values in the range of 39.06-312.5 µg/mL. Furthermore, compound 9 was found to successfully bind to exo-β-(1,3)-glucanase using molecular docking and dynamics simulations run for 500 ns. The physicochemical, pharmacokinetic, and ADMET properties of compounds were also investigated and analyzed by in silico programs.