Synthesis, inhibitory activity and inhibitory mechanism studies of Schiff base Cu(II) complex as the fourth type urease inhibitors

Abstract

Four kinds of Schiff base Cu(II) complexes (the fourth type of novel urease inhibition) were synthesized by the coordination of transition metal Cu(II) ions with aldehyde amine type Schiff base ligands, they were aqua-(5-methoxy-2-((((pyridin-2-yl)methyl)imino)methyl)phenolato-N,N′,O)-(nitrato-O)-copper(II) (1), catena-[(μ2-Isothiocyanato-N,S)-(4-chloro-2-(((pyridin-2-yl)methylimino)methyl)phenolato-N,N′,O)-copper(II)methanol solvate] (2), di-μ-bromobis[1-({[2-(piperidin-1-yl)ethyl]imin o}methyl)naphthalen-2-olato]-di-copper (II)(3) and tetrakis(m-bromo)-bis(m-4-chloro-2-((2-(piper idin-1-yl)ethyl)carbonoimidoyl)phenolato)-tri-copper(II) (4), respectively. The structural characterization of four complexes was performed by Infrared spectrum, Thermogravimetric analysis and X-ray diffraction. The inhibitory effect of complexes on Jack bean urease was studied by phenol red method, the kinetic mechanism of complexes inhibition of urease was investigated by Lineweaver-Burk plot of reciprocal, and the interaction mechanism between complex and urease was discussed by molecular docking. The results showed that IC50 values of four complexes inhibit Jack bean urease are 5.36 μM, 8.01 μM, 2.25 μM and 1.00 μM, respectively, which are much lower than that of the acetohydroxamic acid (27.7 μM) coassayed as a standard urease inhibitor. It has a strong urease inhibitory activity and is a promising urease inhibitor. The inhibitory mechanism of complex 1 and complex 2 on the Jack bean urease belonged to mixed-type inhibition, and the complex 3 and complex 4 is anti-competitive inhibition. Molecular simulation docking calculations show that complexes 3, 4 can form a more stable urease inhibition binding model than complexes 1 and 2 through salt bridges with amino acids, which also theoretically explains the results of experiments on inhibition of urease activity in vitro.