ABSTRACT
A series of fourteen new asymmetrical 1,3-diketone derivatives have been synthesized and evaluated in the ABTS, FRAP and DPPH assays as a new chemotype with antioxidant and drug-like properties. All the compounds displayed low cytotoxicity in comparison to curcumin against the human neuroblastoma SH-SY5Y cell line. Among them, (3Z,5E)-6-(2,5-difluoro-4-hydroxy-phenyl)-1,1,1-trifluoro-4-hydroxyhexa-3,5-dien-2-one (6b) and (3Z,5E)-6-(2,3-difluoro-4-hydroxy-phenyl)-1,1,1-trifluoro-4-hydroxyhexa-3,5-dien-2-one (7b) with excellent solubility and chemical stability in biorelevant media, have also shown a similar Fe+2 chelation behavior to that of curcumin. Additionally, both derivatives 6b and 7b have afforded good neuroprotection activity against H2O2 induced oxidative stress in the same neuronal cell line, with a significant reduction of intracellular ROS levels, in parallel with a good recovery of the Mitochondrial Membrane Potential (ΔΨm). Compounds 6b and 7b with a promising antioxidant and drug-like profile, with low cytotoxic and good neuroprotectant activity, constitute a new interesting chemical class with high potential as new therapeutic agents against neurodegenerative diseases.
Subject(s)
Antioxidants/pharmacology , Iron Chelating Agents/pharmacology , Ketones/pharmacology , Neuroprotective Agents/pharmacology , Quinones/pharmacology , Antioxidants/chemical synthesis , Apoptosis/drug effects , Benzothiazoles/antagonists & inhibitors , Biphenyl Compounds/antagonists & inhibitors , Cell Line, Tumor , Cell Survival/drug effects , Curcumin/pharmacology , Humans , Hydrogen Peroxide/antagonists & inhibitors , Hydrogen Peroxide/pharmacology , Inhibitory Concentration 50 , Iron Chelating Agents/chemical synthesis , Ketones/chemical synthesis , Membrane Potential, Mitochondrial/drug effects , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/chemical synthesis , Oxidative Stress/drug effects , Picrates/antagonists & inhibitors , Quinones/chemical synthesis , Structure-Activity Relationship , Sulfonic Acids/antagonists & inhibitorsABSTRACT
Ionic liquid crystals (ILCs) allow the combination of the high ionic conductivity of ionic liquids (ILs) with the supramolecular organization of liquid crystals (LCs). ILCs salts were obtained by the assembly of long-chained diketonylpyridinium cations of the type [HOOR(n)pyH]⺠and BF4-, ReO4-, NO3-, CF3SO3-, CuCl42- counter-ions. We have studied the thermal behavior of five series of compounds by differential scanning calorimetry (DSC) and hot stage polarized light optical microscopy (POM). All materials show thermotropic mesomorphism as well as crystalline polymorphism. X-ray diffraction of the [HOOR(12)pyH][ReO4] crystal reveals a layered structure with alternating polar and apolar sublayers. The mesophases also exhibit a lamellar arrangement detected by variable temperature powder X-ray diffraction. The CuCl42- salts exhibit the best LC properties followed by the ReO4- ones due to low melting temperature and wide range of existence. The conductivity was probed for the mesophases in one species each from the ReO4-, and CuCl42- families, and for the solid phase in one of the non-mesomorphic Cl- salts. The highest ionic conductivity was found for the smectic mesophase of the ReO4- containing salt, whereas the solid phases of all salts were dominated by electronic contributions. The ionic conductivity may be favored by the mesophase lamellar structure.
ABSTRACT
A series of new (E)-3(5)-[ß-(aryl)-ethenyl]-5(3)-phenyl-1H-pyrazoles bearing fluorine atoms at different positions of the aryl group have been synthesized starting from the corresponding ß-diketones. All compounds have been characterized by elemental analysis, DSC as well as NMR (¹H, (13)C, (19)F and (15)N) spectroscopy in solution and in solid state. Three structures have been solved by X-ray diffraction analysis, confirming the tautomeric forms detected by solid state NMR. The in vitro study of their inhibitory potency and selectivity on the activity of nNOS and eNOS (calcium-calmodulin dependent) as well as iNOS (calcium-calmodulin independent) isoenzymes is presented. A qualitative structure-activity analysis allowed the establishment of a correlation between the presence/ absence of different substituents with the inhibition data proving that fluorine groups enhance the biological activity. (E)-3(5)-[ß-(3-Fluoro-4-hydroxyphenyl)-ethenyl]-5(3)-phenyl-1H-pyrazole (13), is the best inhibitor of iNOS, being also more selective towards the other two isoforms.
Subject(s)
Curcumin/chemistry , Fluorine/chemistry , Nitric Oxide Synthase/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Magnetic Resonance Spectroscopy , Molecular Structure , Nitric Oxide Synthase Type I/antagonists & inhibitors , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide Synthase Type III/antagonists & inhibitors , Pyrazoles/chemistry , Structure-Activity Relationship , X-Ray Diffraction/methodsABSTRACT
A series of ionic bis(pyrazole)-silver(I) and -gold(I) complexes [ML(2)][A] (M = Ag, Au; A = BF(4)(-), PF(6)(-), NO(3)(-)), prepared by coordination of the mesomorphic L = Hpz(2R(n)) or non-mesomorphic L = Hpz(R(n)) pyrazole ligands (Hpz(2R(n)) = 3,5-bis(4-alkyloxyphenyl)pyrazole; Hpz(R(n)) = 3-(4-alkyloxyphenyl)pyrazole), has been studied. The complexes exhibit enantiotropic behaviour, showing smectic A (SmA) mesophases. The choice of the ligands allows the achievement of 'H' or 'U' molecular shapes, which appear to be responsible for the attainment of liquid crystal mesophases, these not being dependent on the coordinating or non-coordinating nature of the A counteranions. The new complexes are photoluminescent both in the solid state and in solution at room temperature. In addition, the luminescent behaviour of selected compounds as a function of the temperature indicates that the luminescence is maintained in the mesophase.
