Zinc complexes of diflunisal: Synthesis, characterization, structure, antioxidant activity, and in vitro and in silico study of the interaction with DNA and albumins

Abstract

From the reaction of ZnCl with the non-steroidal anti-inflammatory drug diflunisal (Hdifl), complex [Zn(difl-O)(MeOH)], 1 was formed, while in the presence of a N,N'-donor heterocyclic ligand 2,2'-bipyridylamine (bipyam), 2,2'-bipyridine (bipy), 1,10-phenanthroline (phen) and 2,2'-dipyridylketone oxime (Hpko), the complexes [Zn(difl-O,O')(bipyam)], 2, [Zn(difl-O,O')(bipy)], 3, [Zn(difl-O,O')(phen)], 4 and [Zn(difl-O)(Hpko)], 5 were isolated, respectively. The complexes were characterized by physicochemical and spectroscopic techniques and the crystal structures of complexes 2, 3 and 5 were determined by X-ray crystallography. The ability of the complexes to scavenge 1,1-diphenyl-picrylhydrazyl, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) and hydroxyl radicals and to inhibit soybean lipoxygenase was studied and the complexes were more active than free Hdifl. The interaction of the complexes with serum albumins was monitored by fluorescence emission spectroscopy and the corresponding binding constants were calculated. UV-vis spectroscopy, viscosity measurements and fluorescence emission spectroscopy for the competitive studies of the complexes with ethidium bromide were employed to investigate the interaction of the complexes with calf-thymus DNA and revealed intercalation as the most possible DNA-binding mode. Computational techniques were used to identify possible binding sites of albumins and DNA, and determine the druggability of human and bovine serum albumins with the five novel complexes. The majority of the complexes are stronger binders than the free Hdifl. This is the first study incorporating experimental and computational results to explore the binding activity of metal-NSAID complexes with DNA and serum albumins, suggesting their application as potential metallodrugs.

Ruthenium–arene complexes with NSAIDs: synthesis, characterization and bioactivity

“…In general, complexes 1-4 are better radical scavengers than the corresponding free NSAIDs Hindo and Hmef, suggesting that their coordination to Ru(II) results in enhanced scavenging activity. In comparison with reported metal-NSAID analogues, 17,22,[29][30][31][32][33][65][66][67][68][69] the present complexes 1-4 are significantly active DPPH-, ABTSand hydroxyl-scavengers and LOX-inhibitors. Although the number of the present compounds is rather low to clarify the structural factors that lead to enhanced antioxidant activity, we suggest that the complexes bearing indomethacin and/or p-cymene are the most potent compounds; as a result, complex 1 was found to be the most active compound.…”

“…The K constants of complexes 1-4 are all relatively high, similar to their respective free NSAIDs, and are in the range of the values calculated for metal-NSAID complexes. 17,22,[29][30][31][32][33][65][66][67][68][69] Among the present complexes, complexes 4 and 1 bear the highest K constants for HSA and BSA, respectively. Considering the structural factors present in complexes 1-4, it seems that complexes 1 and 2 bearing Z 6 -p-cymene ligands show higher binding activity for BSA than their analogues 3 and 4 bearing Z 6 -toluene ligands.…”

“…Furthermore, the complexes are more active scavengers of hydroxyl and ABTS radicals than of DPPH radicals; this scavenging selectivity for hydroxyl and ABTS radicals has been previously reported in the literature, [70][71][72] especially for metal-NSAID complexes. 17,22,[29][30][31][32][33][65][66][67][68][69] Interaction with biomolecules Interaction of the complexes with albumins. The most important role of the serum albumins (SAs) is the transportation of ions and drugs towards their biological targets, i.e.…”

“…The derived k q constants for complexes 1-4 are within the range found for a series of metal-complexes bearing NSAIDs as ligands. 17,22,[29][30][31][32][33][65][66][67][68][69] The SA-binding constants (K) of the complexes have been determined (Table 3) from the corresponding Scatchard plots (Fig. S11 and S12, ESI †) and the Scatchard equation (eqn (S4), ESI †).…”

Mono(2,2′‐bipyridyl)RuII Complex with Four Dimethyl Sulfoxide Ligands as Precursor for cis‐Bis‐heteroleptic RuII Complex: Syntheses, Structures, and Substitution Reactions

“…Because of their unique photophysical and photochemical properties, polypyridyl ruthenium(II) complexes have found many applications in the fields of supramolecular, bio‐inorganic, and catalytic chemistry . Although many heteroleptic polypyridyl ruthenium(II) complexes have been synthesized and investigated, most are of the [Ru(N‐N) 2 (N′‐N′)] 2+ type, in which N‐N and N′‐N′ are bidentate ligands such as 2,2′‐bipyridyl (bpy), 1,10‐phenanthroline (phen), or their analogues , .…”