Nickel(II) complex of polyhydroxybenzaldehyde N4-thiosemicarbazone exhibits anti-inflammatory activity by inhibiting NF-κB transactivation.

BACKGROUND: The biological properties of thiosemicarbazone have been widely reported. The incorporation of some transition metals such as Fe, Ni and Cu to thiosemicarbazone complexes is known to enhance its biological effects. In this study, we incorporated nickel(II) ions into thiosemicarbazone with N4-substitution groups H3L (H; H3L1, CH3; H3L2, C6H5; H3L3 and C2H5; H3L4) and examined its potential anti-inflammatory activity. METHODOLOGY/PRINCIPAL FINDINGS: Four ligands (1-4) and their respective nickel-containing complexes (5-8) were synthesized and characterized. The compounds synthesized were tested for their effects on NF-κB nuclear translocation, pro-inflammatory cytokines secretion and NF-κB transactivation activity. The active compound was further evaluated on its ability to suppress carrageenan-induced acute inflammation in vivo. A potential binding target of the active compound was also predicted by molecular docking analysis. CONCLUSIONS/SIGNIFICANCE: Among all synthesized compounds tested, we found that complex [Ni(H2L1)(PPh3)]Cl (5) (complex 5), potently inhibited IκBα degradation and NF-κB p65 nuclear translocation in LPS-stimulated RAW264.7 cells as well as TNFα-stimulated HeLa S3 cells. In addition, complex 5 significantly down-regulated LPS- or TNFα-induced transcription of NF-κB target genes, including genes that encode the pro-inflammatory cytokines TNFα, IFNß and IL6. Luciferase reporter assays confirmed that complex 5 inhibited the transactivation activity of NF-κB. Furthermore, the anti-inflammatory effect of complex 5 was also supported by its suppressive effect on carrageenan-induced paw edema formation in wild type C57BL/6 mice. Interestingly, molecular docking study showed that complex 5 potentially interact with the active site of IKKß. Taken together, we suggest complex 5 as a novel NF-κB inhibitor with potent anti-inflammatory effects.

1-(2,3,4-Trihydroxy-benzyl-idene)-4-ethyl-thio-semicarbazide.

In the title mol-ecule, C(10)H(13)N(3)O(3)S, the thio-semicarbazide =N-NH-C(=S)-NH- fragment is twisted with respect to the aromatic ring [dihedral angle = 20.5 (1)°]. A weak N-H⋯S hydrogen bond [3.480 (1) Å] links two mol-ecules about a center of inversion to generate a ring. The hydr-oxy groups are engaged in inter-molecular hydrogen bonding; the O-H⋯O and O-H⋯S hydrogen bonds generate a layer motif.

1-(2,3,4-Trihydroxy-benzyl-idene)thio-semicarbazide.

In the title mol-ecule, C(8)H(9)N(3)O(3)S, the thio-semicarbazide =N-NH-C(=S)-NH- fragment is twist a different degree of twist in the three independent mol-ecules [dihedral angles = 7.6 (1), 11.6 (1) and 20.7 (1)°]. Intra-molecular O-H⋯N and O-H⋯O hydrogen bonds occur. In the crystal, the hydr-oxy and amino groups are hydrogen-bond donors and the O-H⋯O, O-H⋯S and N-H⋯O hydrogen bonds generate a layer motif.

{2-[(2-Carbamothiol-ylhydrazin-1-yl-idene-κN,S)meth-yl]-6-hy-droxy-phenolato-κO}(triphenyl-phosphine-κP)nickel(II) chloride.

The deprotonated Schiff base ligand in the title compound, [Ni(C(8)H(8)N(3)O(2)S)(C(18)H(15)P)]Cl, functions as an N,O,S-chelating anion to the phosphine-coordinated Ni atom, which exists in a distorted square-planar geometry. The hy-droxy group forms an intra-molecular O-H⋯O hydrogen bond. The two amino groups of the cation are hydrogen-bond donors to the chloride anion; the hydrogen bonds generate a chain structure running along the b axis.

(E)-1-(2,4,6-Trihy-droxy-benzyl-idene)-4-ethyl-thio-semicarbazide dihydrate.

In the title mol-ecule, C(10)H(13)N(3)O(3)S·2H(2)O, the thio-semi-carbazide =N-NH-C(=S)-NH- fragment [torsion angle = 0.2 (1)°] is nearly coplanar with the benzene ring [dihedral angle = 2.4 (1)°]. The benzene ring and semicarbazide moiety are located on opposite sites of the C=N bond, showing an E configuration. The hy-droxy, imino and water H atoms are engaged in extensive hydrogen bonding, forming a three-dimensional network.

(6-Hydroxy-2-{[2-(N-methyl-carbamo-thiol-yl)hydrazin-1-yl-idene-κN,S]meth-yl}-phenolato-κO)(triphenyl-phosphane-κP)nickel(II) chloride.

The deprotonated Schiff base ligand in the title salt, [Ni(C(9)H(10)N(3)O(2)S)(C(18)H(15)P)]Cl, functions as an N,O,S-chelating anion to the phosphine-coordinated nickel(II) atom, which exists in a distorted square-planar geometry. The hy-droxy group forms an intra-molecular O-H⋯O hydrogen bond. The two amino groups of the cation are hydrogen-bond donors to the chloride anion; the hydrogen bonds generate a chain structure running along the b axis.