Antiureolytic activity of new water-soluble thiadiazole derivatives: Spectroscopic, DFT, and molecular docking studies

Abstract

Two new water-soluble thiadiazole compounds are prepared and characterized with various techniques. These compounds, 5-amino-1,3,4-thiadiazole hydrochloride (1) and 5-amino-3-(N-propane-2-imine)-1,3,4-thiadiazole chloride salt (2) were synthesized via Mannich reaction, and characterized by microelemental analysis, and some spectroscopic means (FTIR, UV-Vis, ¹H NMR, ¹³C NMR and mass), in addition to single-crystal X-ray diffraction for compound 2. DFT calculations were conducted to study their geometry optimization, vibrational spectra, MEP maps, and NBO analysis. In addition, TD-DFT calculations were performed to study their absorption spectra. The prepared compounds were tested against Jack beans urease enzyme (in vitro) to indicate their antiureolytic activity potency. The activity of the enzyme was measured under optimal conditions, before and after mixing with the prepared organic compounds. The results showed that both compounds have potentially inhibited the enzyme activity with respect to their IC₅₀ values: 13.76 µM ± 0.15 for 1, and 18.81 µM ± 0.18 for 2. These values are even lower than that of thiourea (21.40 ± 0.21 µM) as a standard inhibitor. The inhibition activity of urease enzyme was confirmed by a Lineweaver-Burk plot. According to the kinetic parameters obtained from the Lineweaver-Burk plot, the inhibition of urease enzyme by compounds 1 and 2 seems to be non-competitive. Molecular docking studies of the prepared compounds 1 and 2 were performed in order to interpret the obtained biological results and to investigate their interactions with the urease enzyme active site. These studies reveal that compounds 1 and 2 are good candidates as inhibitors for urease enzyme. Moreover, compound 1 exhibits a higher promising inhibition activity.

Keywords: DFT calculations; Molecular docking; Thiadiazole derivatives; Urease inhibitor.