Nitro Substituents Research Articles

Licochalcone A Derivatives as Selective Dipeptidyl Peptidase 4 Inhibitors with Anti-Inflammatory Effects.

A set of 22 analogs of licochalcone A was designed and synthesized to explore their potentials as dipeptidyl peptidase 4 (DPP4) inhibitors with anti-inflammatory effects. The anti-DPP4 effects of these analogs were evaluated using the fluorescent substrate Gly-Pro-N-butyl-4-amino-1,8-naphthalimide (GP-BAN). The nitro-substituted analogue 27 exhibited the most potent activity (Ki = 0.96 μM). A structure-activity relationship investigation revealed that 4-hydroxyl and 5-chloro substituents are essential for DPP4 inhibition, while the 3'-nitro substituent improved both DPP4 inhibition and microsomal stability. Furthermore, compound 27 demonstrated good selectivity for DPP4 over other proteases, including dipeptidyl peptidase 9 (DPP9), thrombin, prolyl endopeptidase (PREP), and fibroblast activation protein (FAP). The cytotoxic effect of 27 was evaluated in cancer cell lines HepG-2 and Caco-2 and in somatic RAW264.7 cells and RPTECs. Compound 27 showed no toxicity to normal cells and weak toxicity to cancer cells. In a living cell imaging assay, 27 blocked the dipeptidase activity of DPP4 in both Caco-2 and HepG-2 cells. This compound also dose-dependently suppressed the expression levels of the chemokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β).

Compressed and Expanded Lattices - Barriers to Spin-State Switching in Mn3+ Complexes.

We report the structural and magnetic properties of two new Mn3+ complex cations in the spin crossover (SCO) [Mn(R-sal2323)]+ series, in lattices with seven different counterions in each case. We investigate the effect on the Mn3+ spin state of appending electron-withdrawing and electron-donating groups on the phenolate donors of the ligand. This was achieved by substitution of the ortho and para positions on the phenolate donors with nitro and methoxy substituents in both possible geometric isomeric forms. Using this design paradigm, the [MnL1]+ (a) and [MnL2]+ (b) complex cations were prepared by complexation of Mn3+ to the hexadentate Schiff base ligands with 3-nitro-5-methoxy-phenolate or 3-methoxy-5-nitro-phenolate substituents, respectively. A clear trend emerges with adoption of the spin triplet form in complexes 1a-7a, with the 3-nitro-5-methoxy-phenolate donors, and spin triplet, spin quintet and thermal SCO in complexes 1b-7b with the 3-methoxy-5-nitro-phenolate ligand isomer. The outcomes are discussed in terms of geometric and steric factors in the 14 new compounds and by a wider analysis of electronic choices of Mn3+ with related ligands by comparison of bond length and angular distortion data of previously reported analogues in the [Mn(R-sal2323)]+ family. The structural and magnetic data published to date suggest a barrier to switching may exist for high spin forms of Mn3+ in those complexes with the longest bond lengths and highest distortion parameters. A barrier to switching from low spin to high spin is less clear but may operate in the seven [Mn(3-NO2-5-OMe-sal2323)]+ complexes 1a-7a reported here which were all low spin in the solid state at room temperature.

Study of the effect nitro and hydroxyl substituents of two imidazopyridines derivatives on inhibitory efficacy: combining theoretical and experimental study (part A)

Study of the effect nitro and hydroxyl substituents of two imidazopyridines derivatives on inhibitory efficacy: combining theoretical and experimental study (part A)

Synthesis and analysis of novel catecholic ligands as inhibitors of catechol-O-methyltransferase

l-DOPA, a dopamine precursor, is commonly used as a treatment for patients with conditions such as Parkinson’s disease. This therapeutic l-DOPA, as well as the dopamine derived from l-DOPA, can be deactivated via metabolism by catechol-O-methyltransferase (COMT). Targeted inhibition of COMT prolongs the effectiveness of l-DOPA and dopamine, resulting in a net increase in pharmacological efficiency of the treatment strategy. Following the completion of a previous ab initio computational analysis of 6-substituted dopamine derivatives, several novel catecholic ligands with a previously unexplored neutral tail functionality were synthesized in good yields and their structures were confirmed. The ability of the catecholic nitriles and 6-substituted dopamine analogues to inhibit COMT was tested. The nitrile derivatives inhibited COMT most effectively, in agreement with our previous computational work. pKa values were used to further examine the factors involved with the inhibition and molecular docking studies were performed to support the ab initio and experimental work. The nitrile derivatives with a nitro substituent show the most promise as inhibitors, confirming that both the neutral tail and the electron withdrawing group are essential on this class of inhibitors.

Diphenyl imidazole-based fluorescent chemosensor for Al3+ and its Al3+ complex toward water detection in food products

A sophisticated fluorescent chemosensor, 2-(4-nitrophenyl)-4,5-diphenyl-1H-imidazole (NPDI), was designed and synthesized through a one-step condensation reaction. NPDI exhibited a fluorescence enhancement response toward Al3+, accompanied by significant emission color change without interference from other tested metal ions. The binding stoichiometry and mechanism was corroborated using various techniques. The limit of detection (LOD) for Al3+ could reach 7.25 × 10−8 mol/L and the binding constant was found to be 1.47 × 105 L/mol. Furthermore, the in-situ formed NPDI·Al complex functioned a secondary chemosensor for water by quenching effect. The fluorescence quenching mechanism could be attributed to hydrogen bonding interaction of nitro substituent with water. The LOD was calculated to be 0.012 %, indicating NPDI·Al heightened sensitivity to water. Additionally, NPDI·Al complex was employed for the moisture detection in the surroundings. Finally, the practical application of NPDI·Al complex had been successfully used in the determination of water content in food products.

Effects of electron-accepting substituents on the fluorescence of oxygen-bridged triarylamine

New electron-accepting oxygen-bridged triphenylamines were synthesized with nitro and dimesitylboryl substituents. Using optical and electrochemical characterization, the effect of electron-withdrawing substituents on quasi-planar triarylamine skeletons was clarified. Compared with the unbridged nitro-substituted triphenylamine reference, the oxygen-bridged structure featured a smaller optical gap, shifting the absorption and fluorescence wavelengths to longer wavelengths. Structural relaxation in the electronically excited state was suppressed, and the Stokes shift was reduced. Replacing the nitro substituent with a dimesitylboryl group resulted in an increase in the fluorescence quantum yield due to the suppression of the vibronic coupling.

Unveiling substituent effects in [3+2] cycloaddition reactions of benzonitrile N-oxide and benzylideneanilines from the molecular electron density theory perspective

The zw- type [3+2] cycloaddition (32CA) reactions of benzonitrile N-oxide with a series of substituted benzylideneanilines have been studied within the Molecular Electron Density Theory (MEDT) at the B3LYP/6-31G(d) computational level. The presence of dimethylamino and methoxy substituents in the aromatic rings of benzylideneaniline makes the reaction more facile relative to the unsubstituted one, while the electron withdrawing nitro substituents relatively induce minimal changes in the energy profile complying with the experimentally observed reaction rates. The presence of non-bonding electron density at the nitrogen atom and the formation of pseudoradical centre at the carbon atom of benzonitrile N-oxide characterise the difference in electronic structure of the TSs relative to the reagents, while the topological analysis of the electron localization function (ELF) and the atoms-in-molecules (AIM) reveal no covalent bond formation at the early TSs. The present MEDT study analyses the experimentally observed substituent effects and complete regioselectivity in the studied 32CA reactions.

Revealing Internal Rotation and 14N Nuclear Quadrupole Coupling in the Atmospheric Pollutant 4-Methyl-2-nitrophenol: Interplay of Microwave Spectroscopy and Quantum Chemical Calculations.

The structure and interactions of oxygenated aromatic molecules are of atmospheric interest due to their toxicity and as precursors of aerosols. Here, we present the analysis of 4-methyl-2-nitrophenol (4MNP) using chirped pulse and Fabry-Pérot Fourier transform microwave spectroscopy in combination with quantum chemical calculations. The rotational, centrifugal distortion, and 14N nuclear quadrupole coupling constants of the lowest-energy conformer of 4MNP were determined as well as the barrier to methyl internal rotation. The latter has a value of 106.4456(8) cm-1, significantly larger than those from related molecules with only one hydroxyl or nitro substituent in the same para or meta positions, respectively, as 4MNP. Our results serve as a basis to understand the interactions of 4MNP with atmospheric molecules and the influence of the electronic environment on methyl internal rotation barrier heights.

Intramolecular Charge Transfer and Ultrafast Nonradiative Decay in DNA-Tethered Asymmetric Nitro- and Dimethylamino-Substituted Squaraines.

Molecular (dye) aggregates are a materials platform of interest in light harvesting, organic optoelectronics, and nanoscale computing, including quantum information science (QIS). Strong excitonic interactions between dyes are key to their use in QIS; critically, properties of the individual dyes govern the extent of these interactions. In this work, the electronic structure and excited-state dynamics of a series of indolenine-based squaraine dyes incorporating dimethylamino (electron donating) and/or nitro (electron withdrawing) substituents, so-called asymmetric dyes, were characterized. The dyes were covalently tethered to DNA Holliday junctions to suppress aggregation and permit characterization of their monomer photophysics. A combination of density functional theory and steady-state absorption spectroscopy shows that the difference static dipole moment (Δd) successively increases with the addition of these substituents while simultaneously maintaining a large transition dipole moment (μ). Steady-state fluorescence and time-resolved absorption and fluorescence spectroscopies uncover a significant nonradiative decay pathway in the asymmetrically substituted dyes that drastically reduces their excited-state lifetime (τ). This work indicates that Δd can indeed be increased by functionalizing dyes with electron donating and withdrawing substituents and that, in certain classes of dyes such as these asymmetric squaraines, strategies may be needed to ensure long τ, e.g., by rigidifying the π-conjugated network.

Substituent effects on aromatic interactions in water.

Molecular recognition in water involves contributions due to polar functional group interactions, partial desolvation of polar and non-polar surfaces and changes in conformational flexibility, presenting a challenge for rational design and interpretation of supramolecular behaviour. Conformationally well-defined supramolecular complexes that can be studied in both water and non-polar solvents provide a platform for disentangling these contributions. Here 1 : 1 complexes formed between four different calix[4]pyrrole receptors and thirteen different pyridine N-oxide guests have been used to dissect the factors that govern substituent effects on aromatic interactions in water. H-bonding interactions between the receptor pyrrole donors and the guest N-oxide acceptor at one end of the complex lock the geometrical arrangement of a cluster of aromatic interactions at the other end of the complex, so that a phenyl group on the guest makes two edge-to-face and two stacking interactions with the four aromatic side-walls of the receptor. The thermodynamic contribution of these aromatic interactions to the overall stability of the complex was quantified by chemical double mutant cycles using isothermal titration calorimetry and 1H NMR competition experiments. Aromatic interactions between the receptor and a phenyl group on the guest stabilise the complex by a factor of 1000, and addition of substituents to the guest phenyl group further stabilises the complex by an additional factor of up to 1000. When a nitro substituent is present on the guest phenyl group, the complex has a sub-picomolar dissociation constant (370 fM). The remarkable substituent effects observed in water for these complexes can be rationalised by comparison with the magnitude of the corresponding substituent effects measured in chloroform. In chloroform, the double mutant cycle free energy measurements of the aromatic interactions correlate well with the substituent Hammett parameters. Electron-withdrawing substituents increase the strength of the interactions by a factor of up to 20, highlighting the role of electrostatics in stabilising both the edge-to-face and stacking interactions. The enhanced substituent effects observed in water are due to entropic contributions associated with the desolvation of hydrophobic surfaces on the substituents. The flexible alkyl chains that line the open end of the binding site assist the desolvation of the non-polar π-surfaces of polar substituents, like nitro, but at the same time allow water to interact with the polar H-bond acceptor sites on the substituent. This flexibility allows polar substituents to maximise non-polar interactions with the receptor and polar interactions with the solvent, leading to remarkably high binding affinities.

Solvent effect on the Spectra of Methylene Green and Methylene Blue.

This investigation focuses on dyes that differ only in the nitro substituent. The NO2 group leads to a strong hardening of the fluorescence at 298K. In methylene green (MG) the excitation energy migrates to the system of triplet states. This non-radiative process causes the MG fuorescence absent or too low compared to methylene blue (MB). Moreover, laser-induced fluorescence is completely absent for MG in the investigated solvents. However, at liquid nitrogen temperature, we recorded fluorescence for MG in ethanol 250 times higher than at room temperature and phosphorescence too. The intensity of the MB fluorescence band in ethanol at 77K is 6 times higher than at room temperature. According to the results of this study, the lifetime in the excited state decreases in the following order: isopropanol > acetonitrile≈ethanol≈dimethyl sulfoxide > > water for MG and chloroform > acetonitrile≈ethanol≈dimethyl sulfoxide > > water≈isopropanol for MB. In addition, MG has phosphorescence in ethanol at 780nm (12,800cm-1) and in chloroform at 810nm (12,300cm-1).

Influence of nitro group on solvatochromism, nonlinear optical properties of 3-morpholinobenzanthrone: Experimental and theoretical study

We report the synthesis of 3-morpholino-9-nitrobenzanthrone (NMB) dye. By using FT-IR, 1H NMR, and X-ray crystallography, we characterized the molecular structure of the synthesized dye. The structural features of the dye were compared to those of an identical dye without nitro substituents. The push pull kind of benzanthrone dye (NMB) was examined for solvent-dependent photophysical properties. NMB exhibits a large Stokes shift. The polarity plots indicate that hydrogen-bonding interactions are influential in most of the solvents. Detailed structural analysis as well as one-photon absorption and emission process was computationally investigated for both the molecules. NMB exhibits significant two photon absorption (TPA) activity at various electron transitions ranging from visible to NIR regions. Further, Nonlinear absorption coefficient was calculated for the dye samples from the open aperture Z-scan data. The nonlinear absorption coefficient values were obtained for the dye samples for input laser pulse energies ranging from 5 to 20 µJ. The results decipher that these dye samples are prospective contenders for the fabrication of optical limiter devices. Nitro substituents at the active site enhance charge transfer, thereby enhancing the NLO response.

Synthesis, biological assessment, and computational investigations of nifedipine and monastrol analogues as anti-leishmanial major and anti-microbial agents.

Leishmaniasis includes a range of parasitic diseases caused by numerous types of the protozoan kinetoplastid parasite. Fungal and bacterial pathogens have led to infectious illnesses causing some main public health problem in current years. A series of dihydropyridine and tetrahydropyrimidine derivatives having fluoro, bromo, and nitro substituents at para-phenyl ring on C4 of dihydropyridine and tetrahydropyrimidine rings were synthesized. Then, anti-leishmanial and antimicrobial potencies of compounds were assessed. All compounds were synthesized via Hantzsch and Biginelli reactions. All derivatives were evaluated for their anti-leishmanial and antimicrobial activities. Moreover, docking and molecular dynamics simulation calculations of the compounds in PRT1 binding site were performed to report the results of anti-leishmanial and antimicrobial activities. Compounds 4a and 4b showed the highest anti-amastigote and anti-promastigote activities. Compound 4a revealed the highest antimicrobial activity against E. coli, P. aeruginosa, and C. albicans strains. In addition, compound 4c showed the highest activity against S. aureus. The fluoro, bromo, and nitro substituents in para-position of phenyl group at C4 of dihydropyridine and tetrahydropyrimidine moieties as well as the bulk and length of the chain linking to the ester moieties are essential for anti-leishmanial and anti-microbial activities of these derivatives. Low cytotoxicity was shown by most of derivatives against macrophages. The molecular docking studies were in agreement with in vitro assay. Moreover, hydrogen binds, RMSF, RMSD, and Rg, strongly showed the steady binding of 4a and 4b compounds in PRT1 active site.

Manipulating Excited State Properties of Iridium Phenylpyridine Complexes with "Push-Pull" Substituents.

We have prepared a series of complexes of the type [IrIII(ppy)2(L]n+ complexes (1-4), where ppy is a substituted 2-phenylpyridine and L is a chelating phosphine thioether ligand. The parent complex (1) comprises an unsubstituted phenylpyridine ligand, whereas complex 2 contains a nitro substituent on the pyridine ring, complex 3 features a diphenylamine group on the phenyl ring, and 4 has both nitro and diphenylamine groups. Crystallographic, 1H NMR, and elemental analysis data are consistent with each of the chemical formulae. DFT (density functional theory) computational results show a complicated electronic structure with contributions from Ir, ppy, and the PS ligand. Ultrafast pump-probe data show strong contributions from the phenylpyridine moieties as well as strong panchromatic excited state absorption transitions. The data show that nitro and/or diphenylamine substituents dominate the spectroscopy of this series of compounds.

Design and synthesis of novel ureido and thioureido conjugated hydrazone derivatives with potent anticancer activity

BackgroundCompounds possessing urea/thiourea moiety have a wide range of biological properties including anticancer activity. On the other hand, taking advantage of the low toxicity and structural diversity of hydrazone derivatives, they are presently being considered for designing chemical compounds with hydrazone moiety in the field of cancer treatment. With this in mind, a series of novel ureido/thioureido derivatives possessing a hydrazone moiety bearing nitro and chloro substituents (4a–4i) have been designed, synthesized, characterized and evaluated for their in vitro cytotoxic effect on HT-29 human colon carcinoma and HepG2 hepatocarcinoma cell lines.ResultsTwo compounds (4c and 4e) having the chloro phenylurea group hybridized with phenyl hydrazone bearing nitro or chloro moieties demonstrated potent anticancer effect with the IC50 values between 2.2 and 4.8 µM at 72 h. The mechanism of action of compound 4c was revealed in hepatocellular carcinoma cells as an inducer of apoptosis in a caspase-independent pathway.ConclusionTaken together, the current work presented compound 4c as a potential lead compound in developing future hepatocellular carcinoma chemotherapy drugs.MethodsThe compounds were synthesized and then characterized by physical and spectral data (FT-IR, 1H-NMR, 13C-NMR, Mass). The anticancer activity was assessed using MTT assay, flowcytometry, annexin-V, DAPI staining and Western blot analysis.Graphical

Push and Pull Effect of Methoxy and Nitro Groups Modifies the Spin-State Switching Temperature in Fe(III) Complexes.

We have explored the impact of electron-donating (methoxy) and electron-withdrawing (nitro) substituents on SalEen ligand based spin crossover (SCO) behavior of Fe(III) complexes. Thus, 3-X-substituted SalEen ligands were employed to prepare [Fe(3-X-SalEen)2]·NCSe, where X = OMe (1), H (2), and NO2 (3) (3-X-SalEen is the condensation product of 3-substituted salicylaldehyde and N-ethylethylenediamine). The characteristic spin transition temperature (T 1/2) is shown to shift to a lower temperature when an electron-donating substituent (OMe) is used and to a higher temperature when an electron-withdrawing substituent (NO2) is used. We used experimental and theoretical methods to determine the reasons for this behavior. The solid-state magnetic data revealed the transition temperatures for complexes 1, 2, and 3 to be 219, 251, and 366 K, respectively. The solution-state magnetic data also support this trend in T 1/2 values. UV-vis spectra analysis indicates that there is greater delocalization in the π-manifold of the ligand when the nitro group is the substituent. Theoretical studies through density functional theory methods suggest the methoxy substituent decreases the energy gap between the t2g and eg orbitals (explaining the lower T 1/2 value), while the nitro substituent increases the energy gap between the t2g and eg orbitals and thus increases the T 1/2 value.

Solvatochromic fluorescent styryl pyrene probes for the quantitative determination of water content in organic solvents

A series of D-π-A fluorescent styryl pyrene probes were synthesized through the Wittig reaction. The introduction of an electron-withdrawing substituent on the phenyl ring creates a push-pull system that shows solvent-dependent intramolecular charge transfer (ICT) and solvatochromic properties. Among these, the styryl pyrene probes with nitro (Py-NO2) and aldehyde (Py-CHO) substituents exhibited remarkable sensitivity to environment polarity. They show remarkable fluorescence changes from green to red, and blue to orange in nonpolar to polar organic solvents, respectively. The results were explained by the Lippert-Mataga and ET(30) models, which were supported by theoretical calculations by the density functional theory (DFT). Importantly, the fluorescence emission of Py-NO2 in organic solvents is sensitive to the presence of water in the range of 0–34.2% (v/v) in THF, 0–9.1% (v/v) in DMF, and 0–39.7% (v/v) in CH3CN. The limits of detection of water were established as low as 0.007%, 0.033%, and 0.036% (v/v) in THF, DMF, and CH3CN, respectively. Py-CHO showed somewhat higher limits of detection than Py-NO2 for the same solvents but exhibited a broad linear response to water content in EtOH between 3.3 and 63.6% (v/v) water content with the limit of detection at 2.350% (v/v). Thus, it is possibly useful as a sensor for the wide range detection of alcohol content in beverages. These push-pull styryl pyrene probes not only served as a new supersensitive fluorescent sensor for the quantitative detection of low to medium-level water content in organic solvents but may also be useful in a broad range of applications.

QSAR Studies on Nitrobenzene Derivatives using Hyperpolarizability and Conductor like Screening model as Molecular Descriptors

Quantitative structure-activity relationship (QSAR) models were useful in understanding how chemical structure relates to the toxicology of chemicals. In the present study, we report quantum molecular descriptors using conductor like screening model (COs) area, the linear polarizability, first and second order hyperpolarizability for modelling the toxicology of the nitro substituent on the benzene ring. All the molecular descriptors were performed using semi-empirical PM6 approaches. The QSAR model was developed using stepwise multiple linear regression. We found that the stable QSAR modelling of toxicology benzene derivatives used second order hyper-polarizability and COs area, which satisfied the statistical measures. The second order hyperpolarizability shows the best QSAR model. We also discovered that the nitrobenzene derivative’s substitutional functional group has a significant effect on the quantum molecular descriptors, which reflect the QSAR model.

Experimental and theoretical investigations on chalcones containing pyrene

Three chalcone derivatives featuring pyrene chromophore are designed, synthesised and studied for their thermal, photophysical and electrochemical properties. They exhibited a maximum absorption peak ranging from 414 nm to 421 nm and emission in cyan region. A chalcone containing nitro substituent displayed intramolecular charge transfer than a similar compound containing methoxy group. Excited lifetime analysis reveals the biexponential decay with two lifetime components. Solvatochromism of the chalcones revealed the effect of auxochrome in the intramolecular charge transfer. All the chalcones exhibited aggregation induced blue-shifted emission due to the restricted rotation and H-aggregation. The density functional theoretical calculation results further confirmed the charge transfer characteristic of the compounds.

Thermochemical study to assess the energetical and structural effects of nitro substituents in methyl benzoate isomers

Combined experimental and computational studies were performed aiming the analysis of energetic properties vs structural characteristics of three methyl nitrobenzoate isomers (methyl 2-nitrobenzoate, M2NB, methyl 3-nitrobenzoate, M3NB, methyl 4-nitrobenzoate, M4NB).The experimental studies include the determination of the enthalpy of formation in the condensed state (crystal and liquid) of the compounds by static combustion, and the determination of enthalpies of phase transition, using Differential Scanning Calorimetry, high temperature Calvet microcalorimetry and the Knudsen effusion method. These data were combined to derive the enthalpy of formation of the methyl nitrobenzoate isomers in the gaseous phase, at T = 298.15 K.At the computational level, the gas-phase enthalpy of formation of the methyl nitrobenzoate isomers were estimated using theoretical approaches, resorting to the G3(MP2)//B3LYP composite method and to appropriate hypothetical gas-phase reactions.The enthalpies of formation obtained experimental and computationally will be discussed and the energetic-structural synergies for the three methyl nitrobenzoate, along with other analogous isomers, will be also analyzed.