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

From the reaction of ZnCl2 with the non-steroidal anti-inflammatory drug diflunisal (Hdifl), complex [Zn(difl-O)(2)(MeOH)(4)], 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')(2)(bipyam)], 2, [Zn(difl-O,O')(2)(bipy)], 3, [Zn(difl-O,O')(2)(phen)], 4 and [Zn(difl-O)2(Hpko)(2)], 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.24 month embargo; Available online 12 February 2017This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Simple physicochemical properties related with lipophilicity, polarity, molecular size and ionization status exert significant impact on the transfer of drugs and chemicals into human breast milk

<p><b>Objectives</b>: The transfer of xenobiotic compounds into human breast milk has raised serious concerns in the last few years. The present study is aimed to assess whether simple physicochemical properties exert significant impact on human breast milk transfer of drugs and chemicals.</p> <p><b>Methods</b>: A large data set of 375 xenobiotic compounds with available experimental milk to plasma (M/P) ratios was systematically compiled from the literature and explored with their physicochemical properties being further analyzed with respect to their extent to transfer into breast milk.</p> <p><b>Results</b>: Xenobiotic compounds with increased breast milk transfer (M/P ≥ 1) were characterized by enhanced lipophilicity and decreased molecular size (<i>p</i> < 0.05). Enhanced polarity and hydrogen bonding capacity were more frequently observed in xenobiotic compounds with reduced breast milk transfer (<i>p</i> < 0.0001). Xenobiotic compounds presenting increased positive charge at pH 7.4 were characterized by enhanced breast milk transfer (<i>p</i> < 0.001). Xenobiotic compounds presenting increased negative charge at pH 7.4 were characterized by decreased breast milk transfer (<i>p</i> < 0.001).</p> <p><b>Conclusions</b>: The present study supports evidence that simple physicochemical properties related with lipophilicity, polarity, molecular size and ionization status exert significant impact on drugs and chemicals transport into human breast milk.</p