Anilino Group Research Articles

Investigation into Protective Groups for Anilino Functionality upon Oxone-Mediated Oxidative Esterification

In the course of organic synthesis, particularly for multi-step synthesis or natural product total synthesis, the selection of appropriate protective groups for the intended functionality is crucial in order to achieve chemoselective synthetic goals. The development of many useful protective groups has been reported based on the functionality of the anilino group. Herein, we discuss our study of various protective groups and the processes we used to establish compatibility with anilino functionality via the implementation of Oxone-mediated oxidative esterification in methanol. The results and the details of our experiments are reported herein.

D 6 h Symmetric Radical Donor–Acceptor Nanographene Modulated Interfacial Carrier Transfer for High-Performance Perovskite Solar Cells

<i>D</i> ^{6 <i>h</i>} Symmetric Radical Donor–Acceptor Nanographene Modulated Interfacial Carrier Transfer for High-Performance Perovskite Solar Cells

Preparation, biological & cheminformatics-based assessment of N2,N4-diphenylpyrimidine-2,4-diamine as potential Kinase-targeted antimalarials

Twenty eight new N2,N4-diphenylpyrimidine-2,4-diamines have been prepared in order to expand our understanding of the anti-malarial SAR of the scaffold. The aim of the study was to make structural modifications to improve the overall potency, selectivity and solubility of the series by varying the anilino groups attached to the 2- and 4-position. We evaluated the activity of the compounds against Plasmodium falciparum (Pf) 3D7, cytotoxicity against HepG2, % inhibition at a panel of 10 human kinases, solubility, permeability and lipophilicity, and human and rat in vitro clearance. 11 was identified as a potent anti-malarial with an IC50 of 0.66 µM at the 3D7 strain and a selectivity (SI) of ~ 40 in terms of cytotoxicity against the HepG2 cell line. It also displayed low experimental logD7.4 (2.27), reasonable solubility (124 µg/ml), good metabolic stability, but low permeability. A proteo-chemometric workflow was employed to identify putative Pf targets of the most promising compounds. Ligand-based similarity searching of the ChEMBL database led to the identification of most probable human targets. These were then used as input for sequence-based searching of the Pf proteome. Homology modelling and molecular docking were used to evaluate whether compounds could indeed bind to these targets with valid binding modes. In vitro biological testing against close human analogs of these targets was subsequently undertaken. This allowed us to identify potential Pf targets and human anti-targets that could be exploited in future development.

Design and synthesis of 4-anilinoquinazolines as Raf kinase inhibitors. Part 1. Selective B-Raf/B-RafV600E and potent EGFR/VEGFR2 inhibitory 4-(3-hydroxyanilino)-6-(1H-1,2,3-triazol-4-yl)quinazolines

This paper presents the design and synthesis of 4-(3-hydroxyanilino)-6-(1H-1,2,3-triazol-4-yl)quinazolines of scaffold 9 as selective B-Raf/B-RafV600E and potent EGFR/VEGFR2 kinase inhibitors. Total 14 compounds of scaffold 9 having different side chains at the triazolyl group with/without fluoro substituents at the anilino group were synthesized and investigated. Among them, 9m with a 2-carbamoylethyl side chain and C-4′/C-6′ difluoro substituents was the most potent, which selectively inhibited B-Raf (IC50: 57 nM) and B-RafV600E (IC50: 51 nM) over C-Raf (IC50: 1.0 μM). Compound 9m also actively inhibited EGFR (IC50: 73 nM) and VEGFR2 (IC50: 7.0 nM) but not EGFRT790M and PDGFR-β (IC50: >10 μM). Despite having good potency for B-Raf and B-RafV600E in the enzymatic assays, 9m was less active to inhibit melanoma A375 cells which proliferate due to constitutively activated B-Raf600E. The inferior activity of 9m for A375 was similar to that of sorafenib (6), suggesting that 9m might bind to the inactive conformations of B-Raf and B-RafV600E. Docking simulations could thus be performed to reveal the binding poses of 9m in B-Raf, B-RafV600E, and VEGFR2 kinases.

The Electrochemical Oxidation of Hydroquinone and Catechol through a Novel Poly-geminal Dicationic Ionic Liquid (PGDIL)-TiO2 Composite Film Electrode.

A novel poly-geminal dicationic ionic liquid (PGDIL)-TiO2/Au composite film electrode was successfully prepared by electrochemical polymerization of 1,4-bis(3-(m-aminobenzyl)imidazol-1-yl)butane bis(hexafluorinephosphate) containing polymerizable anilino groups in the electrolyte containing nano-TiO2. The basic properties of PGDIL–TiO2/Au composite films were studied by SEM, cyclic voltammetry, electrochemical impedance spectroscopy, and differential pulse voltammetry. The SEM results revealed that the PGDIL–TiO2 powder has a more uniform and smaller particle size than the PGDIL. The cyclic voltammetry results showed that the catalytic effect on electrochemical oxidation of hydroquinone and catechol of the PGDIL–TiO2 electrode is the best, yet the Rct of PGDIL–TiO2 electrode is higher than that of PGDIL and TiO2 electrode, which is caused by the synergistic effect between TiO2 and PGDIL. The PGDIL–TiO2/Au composite electrode presents a good enhancement effect on the reversible electrochemical oxidation of hydroquinone and catechol, and differential pulse voltammetry tests of the hydroquinone and catechol in a certain concentration range revealed that the PGDIL–TiO2/Au electrode enables a high sensitivity to the differentiation and detection of hydroquinone and catechol. Furthermore, the electrochemical catalytic mechanism of the PGDIL–TiO2/Au electrode was studied. It was found that the recombination of TiO2 improved the reversibility and activity of the PGDIL–TiO2/Au electrode for the electrocatalytic reaction of HQ and CC. The PGDIL–TiO2/Au electrode is also expected to be used for catalytic oxidation and detection of other organic pollutants containing –OH groups.

Preparation and characterization of a novel poly-geminal dicationic ionic liquid (PGDIL)

1,4-bis(3-(m-aminobenzyl)imidazole-1-yl)butane bis(hexafluorinephosphate), a novel geminal dicationic ionic liquid (GDIL) containing anilino groups has been synthesized to prepare a novel poly-geminal dicationic ionic liquid film by electro-polymerization. The morphology and structure of the PGDIL film were analyzed by SEM and FTIR, and a possible polymerization mechanism of GDIL on an Au electrode surface was determined to be 3D instantaneous nucleation. The existence of polyaniline-like units in the PGDIL chain was confirmed by FTIR, indicating that the anilino groups of GDIL were electro-polymerized on the surface of the Au electrode using the chronoamperometry method. The electrochemical performance of the PGDIL film in phenol was studied by cyclic voltammetry, and it was determined that the PGDIL film electrode promoted enhanced phenol electrocatalysis compared to the untreated Au electrode. This work extends the application range of poly ionic liquids and associates ionic liquids with conductive polymers. Where further studies on other physical and chemical properties of polymers will be necessary.

Structural basis of resistance of mutant RET protein-tyrosine kinase to its inhibitors nintedanib and vandetanib

RET is a transmembrane growth factor receptor. Aberrantly activated RET is found in several types of human cancer and is a target for treating RET aberration-associated cancer. Multiple clinically relevant RET protein-tyrosine kinase inhibitors (TKIs) have been identified, but how TKIs bind to RET is unknown except for vandetanib. Nintedanib is a RET TKI that inhibits the vandetanib-resistant RET(G810A) mutant. Here, we determined the X-ray co-crystal structure of RET kinase domain-nintedanib complex to 1.87 Å resolution and a RET(G810A) kinase domain crystal structure to 1.99 Å resolution. We also identified a vandetanib-resistant RET(L881V) mutation previously found in familial medullary thyroid carcinoma. Drug-sensitivity profiling of RET(L881V) revealed that it remains sensitive to nintedanib. The RET-nintedanib co-crystal structure disclosed that Leu-730 in RET engages in hydrophobic interactions with the piperazine, anilino, and phenyl groups of nintedanib, providing a structural basis for explaining that the p.L730V mutation identified in nine independently isolated cell lines resistant to nintedanib. Comparisons of RET-nintedanib, RET(G810A), and RET-vandetanib crystal structures suggested that the solvent-front Ala-810 makes hydrophobic contacts with a methyl group and aniline in nintedanib and blocks water access to two oxygen atoms of vandetanib, resulting in an energetic penalty for burying polar groups. Of note, even though the p.L881V mutation did not affect sensitivity to nintedanib, RET(L881V) was resistant to nintedanib analogs lacking a phenyl group. These results provide structural insights into resistance of RET mutants against the TKIs nintedanib and vandetanib.

Amino-modified hyper-cross-linked polymers with hierarchical porosity for adsorption of salicylic acid from aqueous solution

The synthesis of functionalized hyper-cross-linked polymers (HCLPs) with hierarchical porosity is anticipated for the efficient and rapid adsorption of aromatic compounds from aqueous solution. Herein two amino groups (primary amino and anilino groups) were employed as the functional groups and uploaded on the HCLPs, and hence amino-modified HCLPs were fabricated and their adsorption was comparatively evaluated from aqueous solution using salicylic acid (SA) as the adsorbate. The results reveal that the uploaded amino groups are greatly helpful for the equilibrium adsorption due to the acid-base interaction. In particular, the hierarchical microporous and mesoporous structure is favourable for the kinetic adsorption due to the rapid diffusion of SA in the mesopore channels.

Nanographenes as electron-deficient cores of donor-acceptor systems

Conjugation of nanographenes (NGs) with electro-active molecules can establish donor-acceptor π-systems in which the former generally serve as the electron-donating moieties due to their electronic-rich nature. In contrast, here we report a series of reversed donor-acceptor structures are obtained by C–N coupling of electron-deficient perchlorinated NGs with electron-rich anilines. Selective amination at the vertexes of the NGs is unambiguously shown through X-ray crystallography. By varying the donating ability of the anilino groups, the optical and assembly properties of donor-acceptor NGs can be finely modulated. The electron-deficient concave core of the resulting conjugates can host electron-rich guest molecules by intermolecular donor-acceptor interactions and gives rise to charge-transfer supramolecular architectures.

Molecular and excited state properties of isomeric scarlet disperse dyes

This work was part of an investigation aimed at characterizing the molecular and excited state properties of currently available disperse dyes developed to provide stability to extensive sunlight exposures when adsorbed on poly(ethylene terephthalate) (PET) fibers. Having completed the characterization of yellow, magenta, and cyan disperse dyes for PET-based fabrics used outdoors, our attention turned to the colors designed to enhance the color gamut of a standard 4-member (cyan/yellow/magenta/black) color set. The present study pertained specifically to the characterization of commercially available scarlet dyes. In this regard, HPLC analysis showed that a scarlet product used for PET coloration was mainly a 70/30 mixture of dyes, and the use of HRMS and single crystal X-ray diffraction analyses indicated that these two dyes were azo compounds derived from isomeric pyridine-based couplers which differed in the location of the primary amino (NH2) and anilino (NHPh) groups attached to the pyridine ring. One dye structure has the NHPh group para to the azo group (Sc2), while the other has that group in the ortho position (Sc3). The presence of either ortho substituent provides photostabilization through intramolecular H-bonding with the azo moiety. Further, results from molecular modeling studies showed that the lower excited state oxidation potential of Sc3 relative to that of Sc2 allows Sc3 to function as an energy quencher for the excited state of Sc2 – through thermodynamically favorable electron transfer.

Sensitive Determination of Toxic Clenbuterol in Pig Meat and Pig Liver Based on a Carbon Nanopolymer Composite

The acidified single-walled carbon nanotubes (SWCNTs) were self-assembled on graphene oxide (GO) and then ultrasonically dispersed in a copolymer, Nafion solution, to form a GO/SWCNTs-Nafion polymer nanocomposite, which was employed to modify glassy carbon electrode (GCE). The surface morphological characteristics of different modified electrodes including bare GCE, GO-Nafion/GCE, and GO/SWCNTs-Nafion/GCE were imaged by scanning electron microscopy. For comparison, the differential pulse voltammetry and cyclic voltammetry behaviors were investigated, showing that the GO/SWCNTs-Nafion polymer composite has strong enhancement effect towards oxidation of clenbuterol (CLB). And the corresponding mechanism has been well discussed. During the reaction process, the anilino group of CLB molecule (1) was firstly oxidized to form a radical cation (2), exhibiting a characteristic oxidation peak (I) at 0.95 V, then two radical cations reacting via head-to-head coupling to form a diphenylamine intermediate (3), which was transformed into a CLB dimmer (4) through an azo bond by intramolecular electrons transferring under low potential, exhibiting a pair of reversible oxidation peak (II) and reduction peak (III). Under the optimum conditions, the composite modified electrode showed linear response to CLB in a concentration range of 1.0 × 10−8~6.0 × 10−6 mol/L with a detection limit of 6.0 × 10−9 mol/L. The modified electrode possessed good selectivity, reproducibility, and stability. In comparison with two routine analytical methods like ELISA kit and high-performance liquid chromatography (HPLC), the electrode can be successfully applied to determination of content of CLB in pig meat and pig liver samples with a recovery rate of 96.4~104.2%, suggesting a promising application in food security field.

In Silico Identification of Novel Erlotinib Analogues Against Epidermal Growth Factor Receptor

Cancer is one of the major health challenges in modern times. Considering its high mortality rate, many proteins that are linked to cancer have been targeted for therapy, with one of them being the epidermal growth factor receptor (EGFR). A drug that is currently in the market for the treatment of non-small cell lung cancer and targets EGFR is erlotinib. In a quest for improved efficacy of erlotinib, herein we report molecular docking studies of thirteen erlotinib analogues by modification of the alkyne and anilino groups, all of which displayed better binding affinity than erlotinib. We identified aziridinyl analogue (S)- 13B: with the best binding energy of all the analogues studied.

Synthesis, physicochemical characterization and anticancer screening of sulfa drug ruthenium complexes as anticancer agent

A new five complexes of ruthenium(III) sulfa drug compounds (sulfanilamide, SD1; sulfacetamide sodium; SD2; sulfadiazine, SD3; sulfamethoxazole, SD4; and sulfadimidine, SD5) were synthesized with Ru:SDn molar ratio of 1:2. The ruthenium(III) complexes were characterized by elemental analyses, IR, UV–vis. spectra, magnetic and thermal instruments. The results of the molar conductance measurements reveal that all the complexes have an electrolytic behavior. The infrared spectra show that the sulfa drug ligands (SD1, SD3, SD4 and SD5) act as a monobasic bidentate chelate through both nitrogen atoms of the anilino and sulfonamido groups. On the other hand, the SD2 ligand acts as monodentate toward Ru(III) ion via nitrogen atom of aniline group only because of sulfonamido group is deprotonated by sodium(I) ion. The spectroscopic results suggest octahedral geometry for all Ru(III) complexes. The molecular structures of the SDn ligands were also discussed using quantum chemical calculations. The kinetic thermodynamic parameters of the essential DTGmax decomposition steps were calculated. The images of scanning electron microscopy (SEM) and transmittance electron microscopy (TEM) show amorphous appearance for all Ru(III) complexes except for SD3 complex of a nano-sized structure that confirmed by the X-ray powder diffraction (XRD) patterns. The electron density and the defect structure of the ruthenium(III) complexes were investigated using the positron annihilation lifetime technique. The antimicrobial activities (bacteria and fungi) of the Ru(III) complexes were assessed in comparison with standers. The evaluation of cytotoxicity of Ru(III) complexes against HCT-116 cell line was performed.

Aluminum complexes with bidentate amido ligands: synthesis, structure and performance on ligand-initiated ring-opening polymerization of rac-lactide.

A series of mononuclear aluminum dimethyl complexes bearing bidentate N-[2-(1-piperidinyl)benzyl]anilino or N-(2-morpholinobenzyl)anilino ligands were synthesized via reactions of the corresponding proligands with trimethylaluminum upon heating, while at ambient temperature two trimethylaluminum adducts with neutral N-[2-(1-piperidinyl)benzyl]aniline proligands were obtained. These complexes were well characterized by NMR spectroscopy, elemental analysis and occasionally by EI-HRMS. The molecular structures of the typical trimethylaluminum adduct 2b and aluminum dimethyl complex 3b were further confirmed by X-ray diffraction studies. All the aluminum dimethyl complexes could effectively initiate the ring-opening polymerization (ROP) of rac-lactide in a well-controlled manner to afford PLAs with narrow molecular weight distributions (PDI = 1.06-1.18). The polymer samples obtained are systematically end-capped with the bidentate ancillary ligands as characterized by (1)H NMR and ESI-TOF mass spectroscopy. Moreover, the introduction of substituent(s) at the ortho-position(s) of the anilino moiety in the ligand results in an obvious decrease in the catalytic activity of the corresponding aluminum complex, and complexes with meta-chloro substituted anilino units show higher activities likely due to the enhanced electrophilicity of the metal centers induced by the anilino groups.

ChemInform Abstract: Synthesis of 2,3‐Disubstituted Quinolines from in situ Generated Imines and Its Enamine Tautomer under Radical Cation Induced Conditions.

Abstract A tandem cyclization/aromatization of anilines and aldehydes was achieved under catalytic radical cation salt induced conditions, producing a series of 2,3-disubstituted quinolines in good yields. In this reaction, the in situ generated imine tautomerizes to enamine, which acts as a dienophile to participate in the tandem cyclization, and further elimination of the anilino group triggers the aromatization of tetrahydroquinolines, avoiding harsh conditions.

Synthesis of 2,3-disubstituted quinolines from in situ generated imines and its enamine tautomer under radical cation induced conditions

A tandem cyclization/aromatization of anilines and aldehydes was achieved under catalytic radical cation salt induced conditions, producing a series of 2,3-disubstituted quinolines in good yields. In this reaction, the in situ generated imine tautomerizes to enamine, which acts as a dienophile to participate in the tandem cyclization, and further elimination of the anilino group triggers the aromatization of tetrahydroquinolines, avoiding harsh conditions.

Initial Processes of Proton Transfer in Salicylideneaniline Studied by Time-Resolved Photoelectron Spectroscopy

Excited-state intramolecular proton transfer (ESIPT) in salicylideneaniline (SA) and selected derivatives substituted in the para position of the anilino group have been investigated by femtosecond time-resolved photoelectron spectroscopy (TRPES) and time-dependent density functional theory (TDDFT). SA has a twisted structure at the energetic minimum of the ground state, but ESIPT is assumed to take place through a planar structure, although this has not been fully established. The TRPES studies revealed that the excited-state dynamics within the S1 band varied significantly with excitation wavelength. At finite temperatures, the ground state was found to sample a broad range of torsional angles, from planar to twisted. At lower photon energies (370 nm), only the planar ground-state molecules were excited, and the excited-state reaction took place within 50 fs. At higher energies (350 and 330 nm), predominantly twisted ground-state molecules were excited: they had to planarize before ESIPT could occur. This process was found to be slower in methylated SA but did not change significantly in the brominated and nitrated SAs. These substitution effects on the decay dynamics can be explained by modifications of the potential barriers, as predicted by the TDDFT calculations, and support the mechanism of a twisting motion of the anilino ring prior to ESIPT. The contribution of another pathway leading to internal conversion within the enol form was found to be minor at the excitation wavelengths considered here.

Initial Processes of Proton Transfer in Salicylideneaniline Studied by Time-Resolved Photoelectron Spectroscopy

Excited state intramolecular proton transfer (ESIPT) in salicylideneaniline (SA) and selected derivatives substituted in para -position of the anilino group has been investigated by femtosecond time-resolved photoelectron spectroscopy (TRPES) and time-dependent density functional theory (TDDFT). The planarity of the molecule was found to be a key parameter to describe ESIPT.

5-Anilino-3-benzylsulfanyl-6-(3-chloroanilino)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

In the title compound, C30H23ClN6OS, the benzyl, the 3-chloro­anilino, the phenyl and the anilino groups form dihedral angles of 85.95 (6), 29.63 (7), 28.55 (1) and 87.48 (6)°, respectively, with the pyrazolo­[3,4-d]pyrimidine unit [maximum deviation = 0.052 (2) Å]. An intra­molecular N—H⋯N hydrogen bond occurs. The crystal structure features N—H⋯O hydrogen bonds.

Synthesis, characterization, screening and docking analysis of 4-anilinoquinazoline derivatives as tyrosine kinase inhibitors

We report here the design and synthesis of a series of 4-anilinoquinazoline derivatives, of which 7 compounds were crystallographically characterized, as epidermal growth factor receptor (EGFR) inhibitors by modifications on the aniline ring or at the 6-alkoxy site of the 6,7-dimethoxy-4-anilinoquinazoline pharmacophore. The relative inhibition efficiency on EGFR of all as-prepared compounds were measured and ordered, and the IC50 values of nine highly active compounds were determined by ELISA. Docking studies indicated that all 4-anilinoquinazoline derivatives could be inserted into the ATP-binding pocket of the EGFR via indirect docking, and that the modifications at the 3′-position of the anilino group and 6-alkoxy site of the quinazoline ring have little interference with the formation of the two essential H-bonds between the N3 of the quinazoline ring and Thr766 through a water molecule, and the N1 of the quinazoline ring and N–H of Met769. The displacing of the phenyl at 4-position with pyridinyl dramatically reduces the activity of the quinazoline pharmacophore, the resulting derivative (10) being the least active compound. The docking results also showed that the formation of new H-bonds between the N–H of the ethylenediamine group linked to the 6-alkoxy site and Asp776/Cys773 in the binding pocket of EGFR makes compounds 19 (IC50=12.1±1.6nM) and 20 (IC50=13.6±0.8nM) the most potent EGFR inhibitors in this class and worthy of further modification to obtain more potent anticancer compounds.