New thiosemicarbazone analogues: synthesis, urease inhibition, kinetics and molecular docking studies

The current research reports the synthesis of a library of thiosemicarbazones (3-16) through a two-step chemical transformation. All the synthesized derivatives were purified and fully characterized through mass spectrometry, NMR spectroscopy (¹H-, and ¹³C-NMR), and IR spectroscopy. All the members of the synthesized library were found to be new except compound 8. The synthesized library was screened for its inhibition potential against the urease enzyme. Almost all the compounds exhibited potent activity with the IC₅₀ = 5.3 ± 0.8 − 15.5 ± 0.6 µM in comparison to the thiourea and acetohydroxamic acid used as standard (IC₅₀ = 21.1 ± 0.2, 20.5 ± 0.4 µM). While significant activity was exhibited by compounds 14 and 15 with the IC₅₀ = 23.6 ± 0.6 and 27.3 ± 1.2 µM. Furthermore, kinetic studies were carried out to determine the inhibition mode and molecular docking was employed to recognize the ligand-enzyme interactions. Thereby, the docking results are well in the direction of the in vitro results. Compounds ((E)-N-(2,5-dichlorophenyl)-2-(4-fluorobenzylidene)hydrazine-1-carbothioamide (3) and (E)-2-(2-chlorobenzylidene)-N-(2-fluorophenyl) hydrazinecarbothioamide (5) were identified as the most potent inhibitors of urease by both the in vitro and in silico studies.