Symmetrical Heterocyclic Cage Skeleton: Synthesis, Urease Inhibition Activity, Kinetic Mechanistic Insight, and Molecular Docking Analyses

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 (<b>3a</b>⁻<b>c</b>), and 1.20 ± 0.52, 3.93 ± 0.45, and 12.87 ± 2.11 µM (<b>4a</b>⁻<b>c</b>). 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 (<b>3a</b> and <b>4a</b>) and their most active metal complexes (<b>3b</b> and <b>4b</b>), 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, <b>3a</b>, <b>4a</b>, and <b>4b</b>, while mixed type inhibition was represented by the compound, <b>3b</b>. Moreover, molecular docking confirmed the binding interactive behavior of <b>3a</b> within the active site of the target protein.