Changes In Substituents Research Articles

Synthesis and Evaluation of [(18) F]-Ammonium BODIPY Dyes as Potential Positron Emission Tomography Agents for Myocardial Perfusion Imaging.

Recently, we demonstrated the potential of a [(18) F]-trimethylammonium BODIPY dye for cardiac imaging. This is the first example of the use of the [(18) F]-ammonium BODIPY dye for positron emission tomography (PET) myocardial perfusion imaging (MPI). In this report, we extend our study to other ammonium BODIPY dyes with different nitrogen substituents. These novel ammonium BODIPY dyes were successfully prepared and radiolabeled by the SnCl4 -assisted (18) F-(19) F isotopic exchange method. The microPET results and the biodistribution data reveal that nitrogen substituent changes have a significant effect on the in vivo and pharmacological properties of the tracers. Of the novel [(18) F]-ammonium BODIPY dyes prepared in this work, the [(18) F]-dimethylethylammonium BODIPY is superior in terms of myocardium uptake and PET imaging contrast. These results support our hypothesis that the ammonium BODIPY dyes have a great potential for use as PET/optical dual-modality MPI probes.

The influence of substituents on cooperativity between CH···π and N···H hydrogen bonds in a T-shaped configuration: X-benzene⊥(FH···pyrazine···HF) complexes as a working model

In the present work, the influence of substituents on cooperativity between CH···π and N···H hydrogen bonds is theoretically investigated in the T-shaped configuration of X-benzene⊥(FH···pyrazine···HF) complexes. The calculations are performed at MP2(FC)/6-311++G(d,p) level of theory. The results indicate that the absolute value of binding energy increases as the substituent changes from strong electron acceptor to strong electron donor. Moreover, cooperative and synergistic energies are computed in the complexes. The energetic data reveal a direct correlation between the electron-donating power of substituents and favorable influences of CH···π and N···H hydrogen bonds on each other. The results of AIM and NBO analyses show that the N···H hydrogen bond is strengthened by going from electron acceptor substituents to electron donor ones. It is also found that Hammett constants can be used to predict cooperative and synergistic effects between CH···π and N···H hydrogen bonds.

Crystal structures of five new substituted tetrahydro-1-benzazepines with potential antiparasitic activity.

Tetrahydro-1-benzazepines have been described as potential antiparasitic drugs for the treatment of chagas disease and leishmaniasis, two of the most important so-called `forgotten tropical diseases' affecting South and Central America, caused by Trypanosoma cruzi and Leishmania chagasi parasites, respectively. Continuing our extensive work describing the structural characteristics of some related compounds with interesting biological properties, the crystallographic features of three epoxy-1-benzazepines, namely (2SR,4RS)-6,8-dimethyl-2-(naphthalen-1-yl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, (1), (2SR,4RS)-6,9-dimethyl-2-(naphthalen-1-yl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, (2), and (2SR,4RS)-8,9-dimethyl-2-(naphthalen-1-yl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, (3), all C22H21NO, and two 1-benzazepin-4-ols, namely 7-fluoro-cis-2-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol, C18H18FNO, (4), and 7-fluoro-cis-2-[(E)-pent-1-enyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol, C15H20FNO, (5), are described. Some peculiarities in the crystallization behaviour were found, involving significant variations in the crystalline structures as a result of modest changes in the peripheral substituents in (1)-(3) and the occurrence of discrete disorder due to the molecular overlay of enantiomers with more than one conformation in (5). In particular, an interesting phase change on cooling was observed for compound (5), accompanied by an approximate fourfold increase of the unit-cell volume and a change of the Z' value from 1 to 4. This transition is a consequence of the partial ordering of the pentenyl chains in half of the molecules breaking half of the -3 symmetry axes observed in the room-temperature structure of (5). The structural assembly in all the title compounds is characterized by not only (N,O)-H...(O,N) hydrogen bonds, but also by unconventional C-H...O contacts, resulting in a wide diversity of packing.

One-pot synthesis and antimicrobial evaluation of novel 3-cyanopyridine derivatives of (−)-β-pinene

A series of novel 3-cyanopyridine derivatives of (−)-β-pinene were designed and synthesized by one-pot four-component domino reactions. The targeted compounds were evaluated for their antimicrobial activity against four bacteria (Klebsiella pneumoniae, Enterobacter aerogenes, Staphylococcus aureus, Staphylococcus epidermidis) and a fungus (Candida albicans). The results showed that most of the minimal inhibitory concentrations (MICs) of these 3-cyanopyridine derivatives against the tested strains was in the range of 15.6–125mg/L. Among these 3-cyanopyridine derivatives, the MICs of compound 5h against S. epidermidis and C. albicans were 15.6mg/L, which revealed that compound 5h featured double fluoro substituents at meta- and para-position was the most active compound. In addition, the preliminary structure–activity relationship analysis indicated that the change of substituents on the pyridine ring and benzene ring of 3-cyanopyridine derivatives was an important factor for inducing antimicrobial activity. This research would promote the development of heterocyclic derivatives of β-pinene with antimicrobial activity.

A Comparative Study on Two Cationic Porphycenes: Photophysical and Antimicrobial Photoinactivation Evaluation.

Over the last decades, the number of pathogenic multi-resistant microorganisms has grown dramatically, which has stimulated the search for novel strategies to combat antimicrobial resistance. Antimicrobial photodynamic therapy (aPDT) is one of the promising alternatives to conventional treatments based on antibiotics. Here, we present a comparative study of two aryl tricationic porphycenes where photoinactivation efficiency against model pathogenic microorganisms is correlated to the photophysical behavior of the porphycene derivatives. Moreover, the extent of photosensitizer cell binding to bacteria has been assessed by flow cytometry in experiments with, or without, removing the unbound porphycene from the incubation medium. Results show that the peripheral substituent change do not significantly affect the overall behavior for both tricationic compounds neither in terms of photokilling efficiency, nor in terms of binding.

Ligand-Mediated "Turn On," High Quantum Yield Near-Infrared Emission in Small Gold Nanoparticles.

Small gold nanoparticles (∼1.4-2.2 nm core diameters) exist at an exciting interface between molecular and metallic electronic structures. These particles have the potential to elucidate fundamental physical principles driving nanoscale phenomena and to be useful in a wide range of applications. Here, we study the optoelectronic properties of aqueous, phosphine-terminated gold nanoparticles (core diameter = 1.7 ± 0.4 nm) after ligand exchange with a variety of sulfur-containing molecules. No emission is observed from these particles prior to ligand exchange, however the introduction of sulfur-containing ligands initiates photoluminescence. Further, small changes in sulfur substituents produce significant changes in nanoparticle photoluminescence features including quantum yield, which ranges from 0.13 to 3.65% depending on substituent. Interestingly, smaller ligands produce the most intense, highest energy, narrowest, and longest-lived emissions. Radiative lifetime measurements for these gold nanoparticle conjugates range from 59 to 2590 μs, indicating that even minor changes to the ligand substituent fundamentally alter the electronic properties of the luminophore itself. These results isolate the critical role of surface chemistry in the photoluminescence of small metal nanoparticles and largely rule out other mechanisms such as discrete (Au(I)-S-R)n impurities, differences in ligand densities, and/or core diameters. Taken together, these experiments provide important mechanistic insight into the relationship between gold nanoparticle near-infrared emission and pendant ligand architectures, as well as demonstrate the pivotal role of metal nanoparticle surface chemistry in tuning and optimizing emergent optoelectronic features from these nanostructures.

Synthesis, fungicidal activity and structure-activity relationships of 3-benzoyl-4-hydroxylcoumarin derivatives.

To develop a coumarin-based fungicide, a series of 3-benzoyl-4-hydroxylcoumarin derivatives were synthesised and their fungicidal activities were evaluated against typical fungi occurring in Chinese agroecosystems. Target compounds were characterised through (1) H NMR, (13) C NMR and high-resolution mass spectrometry. The crystal structure of compound III-21 was determined through X-ray diffraction. Bioassay results indicated that most of the target compounds showed good growth inhibition against all of the fungi tested in vitro. EC50 of the target compounds against Physalospora piricola, Rhizoctonia cerealis, Sclerotinia sclerotiorum and Botrytis cinerea indicated that most of the target compounds displayed comparable activity with that of carbindazim and chlorothalonil in vitro. Among these compounds, the analogue 3-(2-bromo-4-chlorobenzoyl)-4-hydroxylcoumarin (III-21) displayed the optimum growth inhibition against R. cerealis (87.5%) and B. cinerea (82.7%) in vivo at 200 µg mL(-1) concentration; thus, this analogue is a potential inhibitor of pathogenic fungi and a new major compound for further optimisation. The results of analysing the structure-activity relationships demonstrated that changes in substituents on benzene ring A of 3-benzoyl-4-hydroxylcoumarin caused different fungicidal activities and provided original information on the preferential conformation to maintain high activities. The present work demonstrated that 3-benzoyl-4-hydroxylcoumarin derivatives can be used as possible major compounds to develop novel fungicides. © 2015 Society of Chemical Industry.

Concerted Halogen-Bonded Networks with N-Alkyl Ammonium Resorcinarene Bromides: From Dimeric Dumbbell to Capsular Architectures.

N-Alkyl ammonium resorcinarene bromides and 1,4-diiodooctafluorobutane via multiple intermolecular halogen bonds (XB) form different exotic supramolecular architectures through subtle changes of the upper rim substituents. Dimeric dumbbell-like assembly with encapsulated guest molecules is generated with N-benzyl substituents. The N-hexyl groups engender an XB-induced polymeric pseudocapsule and an XB-induced dimeric capsule with entrapped 1,4-dioxane guest molecules. The N-propyl and N-cyclohexyl groups generate deep cavity cavitands. The deep cavity cavitands possess cavities for self-inclusion leading to polymeric herringbone arrangement in one direction and that pack into 3D polymeric arrangement resembling egg crate-like supramolecular networks. These assemblies are studied in solution via NMR spectroscopy and in the solid state via X-ray crystallography.

DFT investigation of the electronic structure of amphetamines: effect of substituent on O and N chemical shielding and electric field gradient tensors

To understand the relationship between the electronic structure of amphetamines and their biological activity, a computational investigation was carried out to characterise the 17O and 14N, electric field gradient (EFG) tensors and nuclear quadrupole coupling constants (NQCC) as well as 17O, 15N, 13C and 1H chemical shielding tensors of amphetamines. Calculation were performed with the B3LYP and PW91P86 density functional theory (DFT) methods with the 6-311++G(d,p) basis set. The anisotropic (Δσ) and isotropic (σiso) shielding are in good agreement with the available experimental data. The results indicate that the EFG and σ at oxygen are insensitive to substitution at the N and C10 positions in amphetamines. In contrast, the nitrogen EFG and σ are quite sensitive towards substituent changes. Furthermore, it was found that EFG tensors are more sensitive than σ tensor to the electron density distribution in amphetamines. Biological activities of amphetamines were found to depend upon the electron density distribution in the region of N atoms.

Electron spin relaxation times and rapid scan EPR imaging of pH-sensitive amino-substituted trityl radicals.

Carboxy-substituted trityl (triarylmethyl) radicals are valuable in vivo probes because of their stability, narrow lines, and sensitivity of their spectroscopic properties to oxygen. Amino-substituted trityl radicals have the potential to monitor pH in vivo, and the suitability for this application depends on spectral properties. Electron spin relaxation times T1 and T2 were measured at X-band for the protonated and deprotonated forms of two amino-substituted triarylmethyl radicals. Comparison with relaxation times for carboxy-substituted triarylmethyl radicals shows that T1 exhibits little dependence on protonation or the nature of the substituent, which makes it useful for measuring O2 concentration, independent of pH. Insensitivity of T1 to changes in substituents is consistent with the assignment of the dominant contribution to spin lattice relaxation as a local mode that involves primarily atoms in the carbon and sulfur core. Values of T2 vary substantially with pH and the nature of the aryl group substituent, reflecting a range of dynamic processes. The narrow spectral widths for the amino-substituted triarylmethyl radicals facilitate spectral-spatial rapid scan electron paramagnetic resonance imaging, which was demonstrated with a phantom. The dependence of hyperfine splittings patterns on pH is revealed in spectral slices through the image.

Effect of meso-substituents on the electronic transitions of BODIPY dyes: DFT and RI-CC2 study

In this work, the influence of substituents on the electronic transitions of model 8-R-BODIPY dyes (R=NMe2, NH2, OH, CH3, H, F, SH, Cl, Br, CF3, CN, and NO2) was investigated theoretically using time-dependent density functional theory (TD-DFT) and ab initio coupled-cluster doubles (CC2) quantum chemical calculations. Quantum chemical modeling shows a direct relationship between the electron donating and electron withdrawing character of substituents expressed by Hammett substituent constants (σp) and changes in energy of the HOMO–LUMO gap modulating spectral shifts of the S0→S1 transition. Good linear correlations of the calculated LUMO energies and σp as well as the shape of the HOMO and LUMO allow to obtain a reasonable explanation for the observed effects of substituents.

On the stability of the RuCl2(triphenylphosphine)2(amine) complexes: Ligand substituent effects of cyclic and acyclic amines

In this investigation we applied the Density Functional Theory to understand the substituent effects of cyclic and acyclic amines on the stability of RuCl2(PPh3)2(amine) complexes. In order to evaluate the relative stability of each complex, we analyzed five conformations considering different positions of the chlorine atoms and the triphenylphosphine ligand: a cis–cis (1), a trans–trans (2), a trans–cis (3), a cis–cis (4) and a cis–trans configuration (5). In addition, eight different amine ligands were considered: two acyclic (ammonia and trimethylamine), two cyclic aliphatic (piperidine and pyrrolidine) and four aromatic amine ligands (pyridine, pyrazine, pyrimidine and pyridazine). All the structures presented a square pyramid geometry, and in all systems the stereoisomer 3 is the most stable arrangement among the five isomers. Among the complexes with cyclic aliphatic amine ligands, the energy gap between arrangements 2 and 3 are the most sensitive to the substituent change. Furthermore, when it is considered the replacement by an aromatic amine, there are a large decrease in the energy difference between the arrangements 2 and 3.

Glycosyl alkoxythioimidates as building blocks for glycosylation: a reactivity study

Structural modifications of the leaving group of S-glycosyl O-methyl phenylcarbamothioates (SNea) involving change of substituents that express different electronic effects led to a better understanding of how the reactivity of these glycosyl donors can be modified by changing the structure of their leaving groups. Mechanistic studies involving the isolation of departed aglycones were indicative of the direct activation of both p-methoxy-SNea and p-nitro-SNea leaving groups via the anomeric sulfur rather than the remote nitrogen atom. The presence of an electron donating substituent (p-methoxy) has a strong effect on the nucleophilicity of the sulfur atom that becomes more susceptible toward the attack of thiophilic reagents, in particular. This key observation allowed to differentiate the reactivity levels of p-methoxy-SNea versus p-nitro-SNea and even unmodified SNea leaving groups. The reactivity difference observed in the series of SNea leaving groups is sufficient to be exploited in expeditious oligosaccharide synthesis via selective activation strategies.

Change of mechanism with a change of substituents for a Zincke reaction

The reaction between N-(2,4-dinitrophenyl)-4-(4-pyridyl)pyridinium chloride and 4-aminothiophenol led to an unexpected displacement of the 2,4-dinitrophenyl group, in contrast with the normal Zincke product formed with other nucleophilic 4-substituted anilines. Evidence for a SET process was obtained from EPR spectra of the reaction mixture.

A novel class of allosteric ligands modulating TRPA1: discovery of a switch in agonist‐antagonist function (1061.7)

TRPA1 functions as a ligand‐gated cation channel in sensory neurons and is an important drug discovery target for identification of novel analgesics. We report identification of a novel structural class of ligands reversibly modulating TRPA1 channel function. Using intracellular calcium measurement and whole cell patch clamp recording of HEK293 cells expressing human TRPA1, we characterized the structure‐activity relationships among a group of amino‐triarylmethane analogs. A minimal structural change switched a full agonist to antagonist and small changes in side chain substituents in the same ring greatly altered affinity among antagonists. The agonists, ALGX‐2014 and ALGX‐2015, only elicited TRPA1 currents when applied extracellularly. Their stimulatory effect was blocked by TRPA1 antagonists and unaffected by substituting the three cysteine residues of TRPA1 critical for covalent stimulation by electrophilic agonists, such as AITC and PGJ2, with alanines, suggesting channel activation occurs in a noncovalent manner. This novel class of allosteric agonists and antagonist ligands also interact with other well‐defined TRPA1 ligands and results suggest a highly conserved binding site among TRPA1 and other members of the thermo‐TRP family which may reside in the channel domain.Grant Funding Source: Supported by NIDA grant (DA031516) to JMH and NIDDK grant (DK081654) to MXZ

Supramolecular spectroscopic and thermal studies of azodye complexes

A series of heterocyclic ligand of copper(II) complexes have been synthesized by the reaction of copper(II) acetate with 5-(4′-derivatives phenylazo)-2-thioxothiazolidin-4-one (HLn) yields 1:1 and 1:2 (M:L) complexes depending on the reaction conditions. The elemental analysis, spectral (IR and ESR), conductance, magnetic measurements, and thermogravimetric analysis (TGA) are used to characterize the isolated complexes. It is found that the change of substituent affects the thermal properties of azodye rhodanine derivatives and their Cu(II) complexes. The molecular and electronic structures of the investigated compounds (HLn) were also studied using quantum chemical calculations. According to intramolecular hydrogen bond leads to increasing of the complexes stability. The data revealed that the coordination geometry around Cu(II) in all complexes (1–4) exhibit a trans square planar by NO monobasic bidentate and the two monobasic bidentate in octahedral complexes (5–7). Electronic, magnetic data and ESR spectra proposed the square planar structure for all complexes (1–4) under investigation. The value of covalency factor (β1∗)2 and orbital reduction factor K accounts for the covalent nature of the complexes. The activation thermodynamic parameters, such as activation energy (Ea), enthalpy (ΔH*), entropy (ΔS*), and Gibbs free energy change of the decomposition (ΔG*) are calculated using Coats–Redfern and Horowitz–Metzger methods.

Uncovering the mechanism for selective control of the visible and near-IR absorption bands in bacteriochlorophylls a, b and g.

Bacteriochlorophylls (BChls) play an important role as light harvesters in photosynthetic bacteria. Interestingly, bacteriochlorophylls (BChls) a, b, and g selectively tune their visible (Qx) and near IR (Qy) absorption bands by the substituent changes. In this paper, we theoretically study the mechanism for the selective control of the absorption bands. Density functional theory (DFT) and time-dependent DFT (TD-DFT) and four-orbital model analyses reveal that the selective red-shift of the Qy band with the substituent change from BChl a to b occurs with the lower-energy shift of the (HOMO, LUMO) excited state directly induced by the molecular-orbital energy changes. In contrast, the Qx band hardly shifts by the cancellation between the higher- and lower-energy shifts of the (HOMO-1, LUMO) excited state directly induced by the molecular-orbital energy changes and configuration interaction, respectively. On the other hand, with the substituent changes from BChl a to g, the Qx band selectively blue-shifts by the larger higher-energy shift of the (HOMO-1, LUMO) excited state directly induced by the molecular-orbital energy shifts than the lower-energy shift due to the configuration interaction. In contrast, the Qy band hardly shifts by the cancellation between the higher- and lower-energy shifts of the (HOMO, LUMO) excited state directly induced by the molecular-orbital energy changes and configuration interaction, respectively. Our work provides the important knowledge for understanding how nature controls the light-absorption properties of the BChl dyes, which might be also useful for design of porphyrinoid chromophores.

1,4-Disilacyclohexa-2,5-diene: a molecular building block that allows for remarkably strong neutral cyclic cross-hyperconjugation

2,3,5,6-Tetraethyl-1,4-disilacyclohexa-2,5-dienes with either four chloro (1a), methyl (1b), or trimethylsilyl (TMS) (1c) substituents at the two silicon atoms were examined in an effort to design rigid compounds with strong neutral cross-hyperconjugation between π- and σ-bonded molecular segments arranged into a cycle. Remarkable variations in the lowest electronic excitation energies, lowest ionization energies, and the first oxidation potentials were observed upon change of substituents, as determined by gas phase ultraviolet (UV) absorption spectroscopy, ultraviolet photoelectron spectroscopy (UPS), and cyclic voltammetry. A particularly strong neutral cyclic cross-hyperconjugation was observed in 1c. Its lowest electron binding energy (7.1 eV) is distinctly different from that of 1b (8.5 eV). Molecular orbital analysis reveals a stronger interaction between filled π(CC) and π(SiR2) group orbitals in 1c than in 1a and 1b. The energy shift in the highest occupied molecular orbital is also reflected in the first oxidation potentials as observed in the cyclic voltammograms of the respective compounds (1.47, 0.88, and 0.46 V for 1a, 1b and 1c, respectively). Furthermore, 1,4-disilacyclohexadiene 1c absorbs strongly at 273 nm (4.55 eV), whereas 1a and 1b have no symmetry allowed excitations above 215 nm (below 5.77 eV). Thus, suitably substituted 1,4-disilacyclohexa-2,5-dienes could represent novel building blocks for the design of larger cross-hyperconjugated molecules as alternatives to traditional purely cross-π-conjugated analogues, and could allow for design of molecules with properties that are not accessible to those that are exclusively π-conjugated.

A fingerprint pair analysis of hERG inhibition data

BackgroundDrugs that bind to the human Ether-a-go-go Related Gene (hERG) potassium channel and block its ion conduction can lead to Torsade de Pointes (TdP), a fatal ventricular arrhythmia. Thus, compounds are screened for hERG inhibition in the drug development process; those found to be active face a difficult road to approval. Knowing which structural transformations reduce hERG binding would be helpful in the lead optimization phase of drug discovery.ResultsTo identify such transformations, we carried out a comprehensive analysis of all approximately 33,000 compound pairs in the Novartis internal database which have IC50 values in the dofetilide displacement assay. Most molecular transformations have only a single example in the data set; however, a few dozen transformations have sufficient numbers for statistical analysis.ConclusionsWe observe that transformations which increased polarity (for example adding an oxygen, or an sp2 nitrogen), decreased lipophilicity (removing carbons), or decreased positive charge consistently reduced hERG inhibition between 3- and 10-fold. The largest observed reduction in hERG was from a transformation from imidazole to methyl tetrazole. We also observe that some changes in aromatic ring substituents (for example hydrogen to methoxy) can also reduce hERG binding in vitro.

Supramolecular spectral studies on metal–ligand bonding of novel quinoline azodyes

A series of novel bidentate azodye quinoline ligands were synthesized with various p-aromatic amines like p-(OCH3, CH3, H, Cl and NO2). All ligands and their complexes have been characterized on the basis of elemental analysis, IR, 1H and 13C NMR data and spectroscopic studies. IR and 1H NMR studies reveal that the ligands (HLn) exists in the tautomeric azo/hydrazo form in both states with intramolecular hydrogen bonding. The ligands obtained contain NN and phenolic functional groups in different positions with respect to the quinoline group. IR spectra show that the azo compounds (HLn) act as monobasic bidentate ligand by coordinating via the azodye (NN) and oxygen atom of the phenolic group. The ESR (g|| and g⊥) and bonding α2 parameters of the copper ion were greatly affected by substituting several groups position of ring of quinoline and p-aromatic ring. The ESR spectra of copper complexes in powder form show a broad signal with values in order g||>g⊥>ge>2.0023. The value of covalency factor β and orbital reduction factor K accounts for the covalent nature of the complexes. All complexes possessed an octahedral and square planar geometry. The thermal properties of the complexes were investigated using TGA and DSC. It is found that the change of substituent affects the thermal properties of complexes.