Inhibition studies of Helicobacter pylori urease with Schiff base copper(ii) complexes

Abstract

Nine new copper(II) complexes derived from various Schiff bases were prepared. They are [Cu₂Br₂(L¹)₂] (1), [Cu(L²)₂]·2NO₃·2CH₃OH (2), [Cu(L³)₂]·2Br (3), [Cu(L⁴)₂] (4), [Cu₂Cl₄(L²)₂] (5), [Cu₂Cl₂(L⁵)₂] (6), [CuL⁶(NCS)] (7), [CuClL⁶]·CH₃OH (8), and [Cu₂(L⁷)₂] (9), where L¹ is the monoanionic form of 2-chloro-N′-(4-diethylamino-2-hydroxybenzylidene)benzohydrazide (HL¹), L² is the zwitterionic form of 4-methyl-2-((3-morpholinopropylimino)methyl)phenol (L²), L³ is the zwitterionic form of 2-bromo-4-chloro-6-((2-(2-hydroxyethylamino)ethylimino)methyl)phenol (L³), L⁴ is the monoanionic form of 2-bromo-4-chloro-6-((cyclopentylimino)methyl)phenol (HL⁴), L⁵ is the monoanionic form of 2-((cyclopropylimino)methyl)-4-methylphenol (HL⁵), L⁶ is the monoanionic form of 4-methyl-2-((pyridin-2-ylmethylimino)methyl)phenol (HL⁶), and L⁷ is the dianionic form of N,N′-bis(5-methylsalicylidene)-1,4-diiminobutane (H₂L⁷). The complexes were characterized by infrared and UV-Vis spectra, and single crystal X-ray diffraction. The Cu atoms in complex 1 display square pyramidal coordination, in complex 5 display trigonal bipyramidal coordination, in complex 9 show tetrahedrally distorted square planar coordination, and in the remaining complexes display square planar coordination. Complexes 2, 3, 5, 7 and 8 show effective urease inhibitory activities, with IC₅₀ values of 0.37 ± 1.22, 0.21 ± 0.97, 0.03 ± 0.78, 0.39 ± 0.58 and 0.76 ± 0.95 μM, respectively. Molecular docking study of the complexes with Helicobacter pylori urease was performed. Complex 5 has the most effective activity against urease, with a mixed competitive inhibition mechanism. The complex interacts with the nickel atom of the urease active center, and with the remaining parts of the complex molecule block the entrance of the urease active pocket.