ABSTRACT
The NMR chemical shifts of two azoles and one benzazole whose crystal structures present polymorphism have been computed using the GIPAW approach. 15 N and 13 C nuclei have been studied. Statistical analysis of the computed 13 C and 15 N chemical shifts indicates that the GIPAW chemical shifts reproduce with a high degree of accuracy those experimentally reported. This methodology can be used to identify other polymorphic crystal structures.
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
The X-ray crystal structure of 2-benzyl-1H-benzimidazole, 2BnBzIm, was determined at 293 K showing no dynamic phenomena (disorder) of any class. On the other hand, some 13 C NMR signals were absent in the CPMAS spectrum (100 MHz, 300 K). We decided to carry out variable-temperature SSNMR and discovered that the missing signals are ortho and meta carbons of the phenyl ring of the benzyl group. Line-shape analysis and the Eyring equation were used to determine the barrier, which was compared with the calculated DFT for the gas phase that it is much lower.
ABSTRACT
The title compound, C11H12N2, is not planar due to the folding of the seven-membered ring. In the crystal, mol-ecules are packed opposite each other to minimize the electronic repulsion but the long inter-molecular distances indicate that no directional contacts are found.
ABSTRACT
A group of 13 curcuminoid pyrazoles was investigated for their cytotoxicity on three tumoral cell lines (HT-29, MCF-7, and HeLa) and one non-tumoral human cell line (HEK-293). The values obtained were compared with those of curcumin. A subset of selected derivatives was also studied for their ability to downregulate expression of the hTERT and c-Myc genes, which are both involved in telomerase activity.
Subject(s)
Curcumin/analogs & derivatives , Curcumin/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/genetics , Pyrazoles/chemistry , Pyrazoles/pharmacology , Telomerase/genetics , Cell Line, Tumor , Cells, Cultured , Curcumin/chemical synthesis , Down-Regulation/drug effects , Humans , Proto-Oncogene Proteins c-myc/biosynthesis , Proto-Oncogene Proteins c-myc/genetics , Pyrazoles/chemical synthesis , Telomerase/biosynthesis , Telomerase/metabolismABSTRACT
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
This paper reports the (1)H, (13)C and (15)N NMR experimental study of five benzimidazoles in solution and in the solid state ((13)C and (15)N CPMAS NMR) as well as the theoretically calculated (GIAO/DFT) chemical shifts. We have assigned unambiguously the "tautomeric positions" (C3a/C7a, C4/C7 and C5/C6) of NH-benzimidazoles that, in some solvents and in the solid state, appear different (blocked tautomerism). In the case of 1H-benzimidazole itself we have measured the prototropic rate in HMPA-d 18.
