Meta-substituted Derivatives Research Articles

Anti-inflammatory effects of para-quinone methide derivatives on ulcerative colitis.

A series of para-quinone methide derivatives were evaluated their anti-inflammatory activity. Through the screening of the lipopolysaccharide (LPS)-induced inflammatory cell model in Raw264.7 cells, it was found that the inhibitory activity of meta-substituted derivatives on NO production was superior to that of ortho- and para-substituted derivatives. Among them, in the inflammatory cell model, the meta-trifluoromethyl substituted para-quinone methide derivative 1i had the best activity in inhibiting LPS-induced excess generation of NO. And 1i could effectively inhibit the increase of ROS in inflammatory cells, the expression of iNOS related to the production of NO, and the expressions of inflammation related initiating protein TLR4, pro-inflammatory cytokines IL-6 and TNF-α, inflammasome NLRP3 and Caspase1. In the dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mouse model, the active derivative 1i could inhibit DSS-induced colon shortening, and reverse DSS-induced pathological changes in colon tissue, such as inflammatory infiltration, structural destruction and crypt disappearance. 1i could effectively inhibit oxidative stress, inflammation and apoptosis in UC mice. Moreover, through the determination of serum biochemical indicators, tissue pathologies and tissue organ indexes, 1i could effectively reverse the damage to mouse liver and kidney caused by DSS, playing a protective role in liver and kidney of mice. In summary, 1i was an effective anti-inflammatory reagent and could be developed as a potential drug for anti-UC.

Confronting positions: para- vs. meta-functionalization in triindole for p-type air-stable OTFTs

The 5,10,15-trihexyl-10,15-dihydro-5H-diindolo[3,2-a:3′,2′-c]carbazole core, namely triindole, is well-known for its prominent hole-transporting properties and air stability. The functionalization of this core is also rather versatile, which allows the modulation of its properties by anchoring targeted scaffolds to different positions, e.g. 3,8,13 (para with respect to the nitrogens), 2,7,12 (analogously meta) or the nitrogen heteroatoms. Therefore, triindole excels as a pivotal semiconductor to be exploited in long-lasting organic thin-film transistors (OTFTs). This report aims to shed light on the effect of functionalizing whether para or meta positions with sulfurated moieties, in the pursuit of an enhanced performance in OTFTs. Remarkably, meta-substituted derivatives outshone their para- counterparts in terms of thermal, optical, intermolecular arrangement and semiconductor properties, claiming mobility values up to 2 × 10−3 cm2 V−1 s−1 and a shelf lifetime beyond the analyzed period of 5 months. Analysis of the thin films by grazing incidence X-ray diffraction (GIRXD) and atomic force microscopy (AFM) revealed that the meta-substitution also induces a higher degree of order and better morphology, further corroborating the potential of this structural approach.

Influence of functional groups in chemical reactivity and optoelectronic properties of novel glycidyl nitrate copolymers (GNCOP): a DFT study.

Nowadays, propulsion materials are receiving increased attention as an important component in electric motors. So, awareness of their chemical reactivity and geometric and electronic structures can help to make materials with higher quality and efficiency. In this study, we have proposed novel glycidyl nitrate copolymers (GNCOPs) and meta-substituted derivatives as propulsion materials. Based on density functional theory (DFT) method, chemical reactivity indices have been calculated for predicting their behavior in burning process. Adding functional groups changes reactivity of the GNCOP compound, especially, in the -CN functional group, chemical potential, chemical hardness, and electrophilicity change -0.374, +0.007, and +1.342eV, respectively. In addition, these compounds have dual properties in interaction with oxygen molecule. Optoelectronic study in time-dependent DFT framework shows that there are three peaks with significant excitations. In conclusion, adding functional group into the GNCOPs can introduce new materials with high energetic properties.

Anti-inflammatory effects of β-ionone-curcumin hybrid derivatives against ulcerative colitis

A series of β-ionone-curcumin hybrid derivatives were designed and chosen to merge the biological characteristics of two parent molecules and to obtain a leading compound with higher biological activity. Through the initial screening, the structure activity relationship of their hybrid derivatives as inhibitors of nitric oxide (NO) production showed that meta-substituted derivatives exhibited the best inhibitory activity, among which 1h was the best one. In lipopolysaccharide-induced Raw264.7 macrophage cells, 1h showed anti-inflammatory activity by inhibiting the productions of NO and reactive oxygen species, the expressions of Interleukin-1β and tumor necrosis factor-α, and the translocation of nuclear factor (NF)-κB from the cytosol to the nucleus. Furthermore, molecular docking simulation displayed that 1h could interact with cluster of differentiation 14 to inhibit the toll-like receptor 4/NF-κB signaling. In dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) of mice, 100 mg/kg of 1h could significantly reduce the colon length shortening and protect against colon injury, liver injury and oxidative stress in DSS-induced UC of mice. Besides, 1h was safety in vivo. In conclusion, 1h was the potential anti-inflammatory agent, and further investigations were underway in our laboratory.

Meta-substituted piperlongumine derivatives attenuate inflammation in both RAW264.7 macrophages and a mouse model of colitis

Piperlongumine (PL) has been showed to have multiple pharmacological activities. In this study, we reported the synthesis of three series of PL derivatives, and evaluation of their anti-inflammatory effects in both lipopolysaccharide (LPS)-induced Raw264.7 macrophages and a dextran sulfate sodium (DSS)-induced mouse model of colitis. Our results presented that two meta-substituent containing derivatives 1–3 and 1–6, in which γ-butyrolactam replaced α,β-unsaturated δ-valerolactam ring of PL, displayed low cytotoxicity and effective anti-inflammatory activity. Molecular docking also showed that the meta-substituted derivative, compared with the corresponding ortho- or para-substituted derivative, had significant interactions with the amino acid residues of CD14, which was the core receptors recognizing LPS. In vitro and in vivo studies, 1–3 and 1–6 could inhibit the expression of pro-inflammatory cytokines, and the excessive production of reactive nitrogen species and reactive oxygen species. Oral administration of 100 mg/kg/day of 1–3 or 1–6 alleviated the severity of clinical symptoms of colitis in mice, and significantly reduced the colonic tissue damage to protect the colonic tissue from the DSS-induced colitis. These results suggested that meta-substituted derivatives 1–3 and 1–6 were potential anti-inflammatory agents, which may lead to future pharmaceutical development.

Energetic characteristics of the substituents in para- and meta-substituted derivatives of benzoic acids

This article is the first attempt to describe substituent effects in terms of total energies of the substituted derivatives of benzoic acid. The key quantity in this attempt is the difference of the total energies of the para and meta conformers. This quantity is then correlated with Hammett substituent constants and with some theoretical parameters of the electronic structure of the substituent. While it was previously unclear that the total energy of a molecule would prove to be a useful quantity in studying substituent effects, our research shows that, indeed, this energetical difference correlates well with other parameters if only they also relate to both of these conformers, that is they are differences of their individual counterparts determined for both of these conformers separately.

Design, Synthesis and Antitumor Assessment of Phenylureas Bearing 5-Fluoroindolin-2-one Moiety.

The development of novel antineoplastic agents remains highly desirable. This study focuses on the design, synthesis, and antitumor evaluation of phenyl ureas bearing 5-fluoroindolin-2-one moiety. Three sets of phenylureas were designed and synthesized and their antiproliferative ability was measured against four human carcinoma cell lines (Hela, Eca-109, A549, and MCF-7) via MTT assay. In vivo anticancer activity was further evaluated in xenograft models of human breast cancer (MCF-7). A total of twenty-one new compounds were synthesized and characterized by means of 1H and 13C NMR as well as HR-MS. Three sets of compounds (1a‒1c, 2a‒2c, and 3a‒3c) were initially constructed, and preliminary antiproliferative activities of these molecules were evaluated against Hela, Eca-109, A549 and MCF-7, highlighting the meta-substituted phenylureas (1a‒1c) as the most cytotoxic set. A series of meta-substituted phenylureas derivatives (1d‒1o) were then designed and synthesized for structure-activity relationship study. Most of the new compounds showed desirable cytotoxicity, among which compound 1g exhibited the most remarkable cytotoxic effects against the tested human cancer cells with IC50 values ranging from 1.47 to 6.79 μM. Further studies showed that compound 1g suppressed tumor growth in human breast cancer (MCF- 7) xenograft models without affecting the body weight of its recipients. In this study, twenty-one new compounds, containing the privileged structures of phenylurea and 5-fluoroindolin-2-one, were designed and synthesized. Subsequent structureactivity studies showed that 1g was the most bioactive antitumor agent among all tested compounds, hence a potentially promising lead compound once given further optimization.

Blue-Light Photocleavable Protecting Groups Based on Benzothiadiazole Scaffolds.

An unexpected nucleophilic aromatic substitution lead to a novel benzothiadiazole scaffold that bore the functional group pattern associated with benzyl-type photocleavable protecting groups. The new molecules display efficient photochemical release of leaving groups with blue light. The performance of both ortho- and meta-substituted derivatives was probed through both structural manipulation and computational metrics to improve performance.

Preparation of chiral alcohols by enantioselective reduction of prochiral ketones with Sinapis alba seeds as biocatalyst

The objective of this work is to apply yellow mustard seeds in the enzymatic reduction (biocatalysis) of acetophenone and its derivatives, providing a new biocatalyst for this type of reduction. The reaction parameters were optimized from acetophenone, resulting in 1-phenylethanol, with 68.5% conversion yield and 53% enantiomeric excess (e.e.), analyzed by GC and HPLC, respectively. Reactions to acetophenone and its derivatives were conducted in aqueous medium using buffers pH 6.0 and pH 6.5 in the presence of PVP. A polymer that can act as a protector preventing oxidation of peroxidase enzymes. The results for the derivatives presented low yields (4–18%: substances 5, 7 and 8), moderate (28–40%: substances 3, 4 and 6) and optimum (81%: substance 2) yields, with enantiomeric excesses varying from good to excellent results. Meta-substituted derivatives showed inversion of configuration in the presence of PVP. The biocatalyst was also tested in reactions with other carbonyl compounds, presenting moderate results. In this way, this work offers a new perspective of the application of PVP in biocatalysis reactions and a new biocatalyst for future applications.

Minimal Structural Changes Determine Full and Partial Nicotinic Receptor Agonist Activity for Nicotine Analogues.

Neuronal α4β2 nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels (LGIC) that have been implicated in nicotine addiction, reward, cognition, pain disorders, anxiety, and depression. Nicotine has been widely used as a template for the synthesis of ligands that prefer α4β2 nAChRs subtypes. The most important therapeutic use for α4β2 nAChRs is as replacement therapy for smoking cessation and withdrawal and the most successful therapeutic ligands are partial agonists. In this case, we use the N-methylpyrrolidine moiety of nicotine to design and synthesize new α4β2 nicotinic derivatives, coupling the pyrrolidine moiety to an aromatic group by introducing an ether-bonded functionality. Meta-substituted phenolic derivatives were used for these goals. Radioligand binding assays were performed on clonal cell lines of hα4β2 nAChR and two electrode voltage-clamp experiments were used for functional assays. Molecular docking was performed in the open state of the nAChR in order to rationalize the agonist activity shown by our compounds.

A new class of flavonoids bearing macrocyclic polyethers by stereoselective photochemical cycloaddition reaction

A new class of flavonoids bearing cyclic polyethers involving a phenyl ring was conveniently provided by the intramolecular photochemical dimerization of 2-chromonecarboxylic esters. Irradiation of 2-chromonecarboxylate with a polyether tethered at both ends promoted intramolecular [2 + 2] cyclobutane formation leading to 14- to 27-membered cyclic polyethers. The efficiency depended on the substituted position of the phenyl ring, with ortho- and meta-substituted derivatives giving cycloadducts in good chemical yields and quantum efficiencies, whereas the para-derivatives were inert toward photolysis. X-ray crystallographic analysis revealed that the stereochemistry of the macrocyclic cycloadducts exhibited C2-symmetry.

HPLC–UV assay for the evaluation of inhibitors of plasma amine oxidase using crude bovine plasma

Recently, we have described a method for evaluation of plasma amine oxidase (PAO) inhibitors, which monitors the formation of 6-(5-phenyl-2H-tetrazol-2-yl)hexanal from the corresponding amine substrate by HPLC with UV-detection using purified bovine PAO. We now investigated, whether crude bovine plasma can be used as enzyme source in this assay instead of the purified enzyme. With the aid of specific inhibitors, it was ensured that there was no detectable activity of other important amine oxidases in the plasma, namely monoamine oxidase (MAO) A and B and diamine oxidase (DAO). For a series of ω-(5-phenyl-2H-tetrazol-2-yl)alkan-1-amine substrates similar conversion rates were measured for both the purified PAO and crude plasma. The inhibition values determined for the PAO inhibitor 2-(4-phenylphenyl)acetohydrazide (16) under different conditions also corresponded. Additionally, inhibition data of the known PAO inhibitor 2-amino-N-(3-phenylbenzyl)acetamide (17) and a newly synthesised meta-substituted derivative of 16 were determined, which together reflect the two-step inhibition mechanism of these covalent inhibitors.

Primaquine hybrids as promising antimycobacterial and antimalarial agents

Four series of primaquine (PQ) derivatives were screened for antitubercular and antiplasmodial activity: amides 1a-k, ureas 2a-s, semicarbazides 3a-c and bis-ureas 4a-u. Antimycobacterial activity of PQ derivatives against Mycobacterium tuberculosis (MTB), M. avium complex (MAC) and M. avium subsp. paratuberculosis (MAP) were evaluated in vitro and compared with PQ and the standard antitubercular drugs. In general, the PQ derivatives showed higher potency than the parent compound. Most of the compounds of series 1 and 2 showed high activity against MAP, comparable or even higher than the relevant drug ciprofloxacin, and weak or no activity against MTB and MAC. bis-Trifluoromethylated cinnamamide 1k showed low cytotoxicity and high activity against all three Mycobacterium species and their activities were comparable or slightly higher than those of the reference drugs. PQ urea derivatives with hydroxyl, halogen and trifluoromethyl substituents on benzene ring 2f-p exerted very strong antimycobacterial activity towards all tested mycobacteria, stronger than PQ and the relevant standard drug(s). Unfortunately, these compounds had relatively high cytotoxicity, except bromo 2l and trifluoromethyl 2m, 2n derivatives. In general, meta-substituted derivatives were more active than analogues para-derivatives. Phenyl ureas were also more active than cycloalkyl or hydroxyalkyl ureas. Semicarbazide 3a showed similar activity as PQ, while the other two semicarbazides were inactive. Bis-urea derivatives 4 were generally less active than the urea derivatives sharing the same scaffold, differing only in the spacer type. Out of 21 evaluated bis-urea derivatives, only p-Cl/m-CF3 phenyl derivative 4p, benzhydryl derivatives 4t and 4u and bis-PQ derivative 4s showed high activity, higher than all three reference drugs. After comparison of activity and cytotoxicity, urea 2m and bis-urea 4u could be considered as the most promising agents. Antimalarial potential of PQ derivatives in vitro against the liver stage of P. berghei was evaluated as well. 3-(4-Chlorophenyl)-1-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]urea (4l) was the most active compound (IC50 = 42 nM; cytotoxicity/activity ratio >2000). Our results bring new insights into development of novel anti-TB and antimalarial compounds.

Electron–nuclear motions in a series of meta-substituted iodobenzene derivatives as probed by 127I NQR

A relation between the quadrupole coupling constant e2Qqzz and asymmetry parameter η has been found for a series of meta-substituted iodobenzene derivatives. The relationships e2Qqzz(η) for electrondonor and electron-acceptor substituents have the same form but different numerical values of parameters. The average time of full electron transfer via tunneling has been evaluated.

Photophysical properties and photochemistry of substituted cinnamates and cinnamic acids for UVB blocking: effect of hydroxy, nitro, and fluoro substitutions at ortho, meta, and para positions

Photophysical properties and photochemistry of various substituted cinnamates and cinnamic acids for ultraviolet B blocking were investigated experimentally and theoretically. This series includes monohydroxy, -nitro, and -fluoro derivatives. The absorption spectra were satisfactorily reproduced by the direct SAC-CI method with respect to the peak position and intensity. The transition character of the low-lying two ππ* and σπ* states for these 18 derivatives was analyzed. The para derivatives have a different transition character of the ππ* transitions compared with those of the ortho and meta derivatives. To elucidate the relaxation mechanism, the emission spectra were observed with oxygen quenching and the photostability was examined experimentally. The calculated radiative lifetimes indicate that the ortho- and meta-substituted derivatives have longer lifetimes for emission than the para derivatives. The potential energy curves of the first and second singlet excited states of the hydroxy derivatives as well as the vertical singlet and triplet transitions were examined to investigate the relaxation qualitatively. The ortho and meta derivatives have an energy barrier or flat surface in S1 resulting in fluorescence, whereas the para derivatives show nonradiative decay without an energy barrier. The para-hydroxy derivative was found to be an excellent UV absorber based on its broad absorption in the UVB/UVA regions, less emission, and higher photostability.

ChemInform Abstract: Synthesis and Photophysical Properties of Alkoxysilyl Derivatives of Dibenzoylmethanatoboron Difluoride.

Alkoxysilyl derivatives of dibenzoylmethanatoboron difluoride (DBMBF2) are synthesized by the hydrosilylation reaction of the corresponding O-allyl derivatives of DBMBF2 with triethoxysilane. The photophysical properties of the synthesized O-allyl and alkoxysilyl derivatives are investigated. It is found that the absorption and fluorescence spectra of the DBMBF2 derivatives essentially depend on the position of the O-allyl or O-propyl alkoxysilyl substituent. The highest fluorescence quantum yield is obtained for the para-position, whereas the substitution at the meta-position gives the largest bathochromic shift in the fluorescence spectrum. Density functional theory calculations of the structures and time-dependent density functional theory calculations of the gas-phase excitation and emission energies of alkoxysilyl derivatives are performed at the PBE0/SVP level of theory. Some spectral features of para-, ortho-, and meta-substituted derivatives can be adequately explained by the overlapping of two absorption bands.

Correlation of substituted aromatic β‐diketones' characteristic protons chemical shifts with Hammett substituent constants

Influence of dibenzoylmethane's substituents in meta and para positions on chemical shift values of tautomers' characteristic protons was investigated in four solvents with (1)H NMR spectroscopy: acetone-d(6), benzene-d(6), CDCl(3) and deuterated dimethyl sulfoxide (DMSO-d(6)). It was proved that the influence of substituents on chemical shifts strongly depends on the kind of the solvent; the greatest changes were observed in benzene-d6 and the smallest in CDCl(3). In acetone-d(6) and DMSO-d(6), the influence of substituents on chemical shifts is similar and the most regular. It allowed a fair correlation of chemical shifts of para-substituted dibenzoylmethane derivatives' characteristic protons with Hammett substituent constants in these solvents. In CDCl(3), characteristic protons' chemical shifts were near (1)H NMR spectroscopy measurement error limits, and, therefore, correlation with Hammett substituent constants in this solvent was unsatisfactory. In benzene, although the changes of chemical shifts are the most evident, the changes are also the most irregular, and, therefore, correlation in this solvent failed completely. Results of meta-substituted derivatives were much more irregular, and their correlation with Hammett substituent constants was poor in all investigated solvents.

Synthesis and Photophysical Properties of Alkoxysilyl Derivatives of Dibenzoylmethanatoboron Difluoride

Alkoxysilyl derivatives of dibenzoylmethanatoboron difluoride (DBMBF2) are synthesized by the hydrosilylation reaction of the corresponding O-allyl derivatives of DBMBF2 with triethoxysilane. The photophysical properties of the synthesized O-allyl and alkoxysilyl derivatives are investigated. It is found that the absorption and fluorescence spectra of the DBMBF2 derivatives essentially depend on the position of the O-allyl or O-propyl alkoxysilyl substituent. The highest fluorescence quantum yield is obtained for the para-position, whereas the substitution at the meta-position gives the largest bathochromic shift in the fluorescence spectrum. Density functional theory calculations of the structures and time-dependent density functional theory calculations of the gas-phase excitation and emission energies of alkoxysilyl derivatives are performed at the PBE0/SVP level of theory. Some spectral features of para-, ortho-, and meta-substituted derivatives can be adequately explained by the overlapping of two absorption bands.

The Se–H bond of benzeneselenols (ArSe-H): Relationship between bond dissociation enthalpy and spin density of radicals

Bond dissociation enthalpies (BDE) of benzeneselenol (ArSe-H) and its para and meta-substituted derivatives are calculated using the (RO)B3LYP/6-311++G(2df,2p)//(U)B3LYP/6-311G(d,p) procedure. The computed BDE(Se–H)=308±8kJ/mol for the parent PhSe-H is significantly smaller than the experimental value of 326.4±16.7kJ/mol [Kenttamaa and coworkers, J. Phys. Chem. 100 (1996) 6608] but larger than a previous value of 280.3kJ/mol [Newcomb et al., J. Am. Chem. Soc. 113 (1991) 949]. The substituent effects on BDE’s are analyzed in terms of a relationship between BDE(Se–H) and Mulliken atomic spin densities at the Se radical centers of ArSe (π radicals). Good correlations between Hammett’s substituent constants with BDE(Se–H) are established. Proton affinity and ionization energy amount to PA(C6H5SeH)=814±4kJ/mol and IE(C6H5SeH)=8.0±0.1eV. IEs of the substituted benzeneselenols are also determined. Calculated results thus suggest that 4-amino-benzeneselenol derivatives emerge as efficient antioxidants.

Substituent Effect on the Acid-Promoted Hydrolysis of 2-Aryloxazolin-5-one: Normal vs Reverse

Computational investigations on the acid-promoted hydrolysis of 2-aryl-4,4-dimethyloxazolin-5-one (AMO) and its seven para- and meta-substituted derivatives (with electron-donating groups R = OH, OCH(3), CH(3) and electron-withdrawing groups R = Cl, m-Cl, CF(3), NO(2)) were presented by the density functional theory (B3LYP) method. Two types of reaction mechanism, N-path and O-path, are taken into account, in which the attacks by water molecules at the C2 and C5 are accelerated after the protonation on N3 and carbonyl oxygen atoms, respectively. Our computational results clearly manifest that the hydrolysis of AMOs has an obvious substituent effect at the para and meta positions of the benzene ring by correlating the barrier heights with the Hammett constants of substituents. Furthermore, the N-path shows a normal substituent effect, while the favorable O-path shows a reverse substituent effect. The observed reverse substituent effect in experiment actually springs from the reverse substituent effect of the O-path, not the N-path. The substituent effect of the N-path and O-path can be explained by the electrostatic potential at nuclei (EPN) values and Fukui function, respectively. Our theoretical data provided will allow for a better understanding of the acid-promoted hydrolysis mechanism and the observed reverse substituent effect of the AMOs, in nice agreement with the available experimental conclusion.