Abstract
The present study focuses on the design and synthesis of a cage-like organic skeleton containing two triazole rings jointed via imine linkage. These molecules can act as urease inhibitors. The in-vitro urease inhibition screening results showed that the combination of the two triazole skeleton in the cage-like morphology exhibited comparable urease inhibition activity to that of the reference thiourea while the metallic complexation, especially with copper, nickel, and palladium, showed excellent activity results with IC50 values of 0.94 ± 0.13, 3.71 ± 0.61, and 7.64 ± 1.21 (3a–c), and 1.20 ± 0.52, 3.93 ± 0.45, and 12.87 ± 2.11 µM (4a–c). However, the rest of compounds among the targeted series exhibited a low to moderate enzyme inhibition potential. To better understand the compounds’ underlying mechanisms of the inhibitory effect (3a and 4a) and their most active metal complexes (3b and 4b), we performed an enzymatic kinetic analysis using the Lineweaver–Burk plot in the presence of different concentrations of inhibitors to represent the non-competitive inhibition nature of the compounds, 3a, 4a, and 4b, while mixed type inhibition was represented by the compound, 3b. Moreover, molecular docking confirmed the binding interactive behavior of 3a within the active site of the target protein.
Highlights
The development of competitive and non-competitive enzyme inhibitors based on a metalloskeleton has attracted wide interest of the scientific community because metal ions are found in the active sites of a large number of metalloproteins, such as hemocyanin, and in metalloenzymes, like ureases, tyrosinase, laccase, and ascorbate oxidase [1,2,3,4,5,6,7,8]
Besides current urease inhibitors [16], we aimed to investigate the effect of the two triazole ring structure mutually coupled with each other toward urease inhibition as well as to understand the effect of metal complexation toward the bio-profile of the designed nucleus
The chloride salts of the transition metals were obtained from Aldrich and Alfa Aesar
Summary
The development of competitive and non-competitive enzyme inhibitors based on a metalloskeleton has attracted wide interest of the scientific community because metal ions are found in the active sites of a large number of metalloproteins, such as hemocyanin, and in metalloenzymes, like ureases, tyrosinase, laccase, and ascorbate oxidase [1,2,3,4,5,6,7,8]. Molecules 2019, 24, 312 by the metallocompouds is due to the reaction of the organic skeleton as well as the transition metal ions with the sulfhydryl group in the active center of the enzyme [9]. Compounds with thiol functional groups inhibit urease competitively in their thiolate anion form, R-S− [13]. Imine derivatives of organic compounds have been extensively employed as ligands for several ions, and have been utilized as pigments, catalysts, drugs, and polymer stabilizers [14]
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