Phenylamino Group Research Articles

Synthesis of N-substituted 4-phenyl-2-aminothiazole derivatives and investigation of their inhibition properties against hCA I, II, and AChE enzymes

In this study, thiazole derivatives containing sulphonamide, amide, and phenyl amino groups were synthesized to protect the free amino groups of 5-methyl-4-phenyl-2-aminothiazole and 4-phenyl-2-aminothiazole. Halogenated reactions of N-protected thiazole derivatives have been investigated. LCMS, FT-IR, 1H NMR, and 13C NMR spectroscopy techniques were used to elucidate the structures of the synthesized compounds. Inhibition effects of the N-protected thiazole derivatives against human carbonic anhydrase I, II (hCA I, hCA II), and acetylcholinesterase (AChE) were investigated. The best results among the synthesized N-protected thiazole derivatives showed Ki values in the range of 46.85–587.53 nM against hCA I, 35.01–578.06 nM against hCA II, and in the range of 19.58–226.18 nM against AChE. Furthermore, in silico studies with the target enzyme of the thiazole derivatives (9 and 11), which showed the best results experimentally, have examined the binding interactions of the related compounds at the enzyme active site.

Carboranylphosphines: B9-Substituted Derivatives with Enhanced Reactivity for the Anchoring to Dendrimers.

Several ortho-carboranes bearing a phenoxy or a phenylamino group in the B9 position were prepared employing various protection and deprotection strategies. Following established protocols, dendritic compounds were synthesized from a hexachlorocyclotriphosphazene or thiophosphoryl chloride core, and possible anchoring options for the B9-substituted ortho-carboranes were investigated experimentally and theoretically (DFT). Furthermore, 1- or 1,2-phosphanyl-substituted carborane derivatives were obtained. The resulting diethyl-, diisopropyl-, di-tert-butyl-, diphenyl- or diethoxyphosphines bearing a tunable ortho-carborane moiety are intriguing ligands for future applications in homogeneous catalysis or the medicinal sector.

Thiosuccinimide enabled S-N bond formation to access N-sulfenylated sulfonamide derivatives with synthetic diversity.

A thiosuccinimide enabled S-N cross-coupling strategy has been established for the intermolecular N-sulfenylation of clinically approved sulfa drugs under additive-free conditions. This approach features simple operation, high chemoselectivity for sulfenylating the phenylamino group of sulfonamides, wide substrate scope, and easy scale production, affording N-sulfenylated products in moderate to excellent yields (up to 90%). In addition, we also found that this transformation can be realized in a one-pot manner by employing readily available thiols as starting materials, and the obtained sulfonamide derivatives are capable of various late-stage functionalizations, including oxidation, arylation, benzylation, and methylation.

A Synthetic Strategy for Multi-Functionalized Phospharhodamines via Catalytic P-Arylation

Abstract The visualization of complex biological events in living cells is highly reliant on the development of sophisticated fluorescent probes with multiple functions. Herein, we report a general synthetic strategy for the synthesis of near-infrared-emissive phospharhodamines (PORs) bearing various types of aryl groups on their bridging phosphorus atoms. This versatile approach utilizes a Ni-catalyzed P-arylation that allows for the design of POR-based multi-functionalized fluorescent probes. We found that PORs substituted with an aminophenyl group exhibited pH-responsive fluorescence intensity, where photoinduced electron transfer occurs to quench the fluorescence. The combination of our new approach with conventional modification at the 9-position of the xanthene skeleton facilitates the development of multi-functionalized fluorescent probes. As one demonstration of this method, we synthesized a fluorescence probe that can selectively visualize the lysosomes that result from endosomal maturation.

Photophyical and photosensitizing properties of BODIPYs substantially changed by alkyl- and phenyl-amino groups on meso carbon

meso-RNH (R = C3H7, C4H9, PhCH2, H, and Ph) substituted BODIPY compounds have been prepared to examine their photophysical properties and photosensitizing abilities. We have measured the UV–vis absorption, steady state and time resolved fluorescence, excited triplet state formation using laser flash photolysis, singlet oxygen generation ability using chemical trapping method. The results show that the presence of meso-RNH leads to large blue shift of absorption and emission wavelength, remarkable decrease in fluorescence quantum yield and lifetime values, and significant increase in singlet oxygen formation quantum yield. Quantum chemical calculation also reveals the photoinduced charge transfer (PCT) mechanism. We conclude that property changes are due to: 1) S0 and S1 geometry, 2) ground state structural isomerization, and 3) intramolecular PCT. These results and mechanisms are helpful for designing new functional materials.

Overcoming C60-induced interfacial recombination in inverted perovskite solar cells by electron-transporting carborane

Inverted perovskite solar cells still suffer from significant non-radiative recombination losses at the perovskite surface and across the perovskite/C60 interface, limiting the future development of perovskite-based single- and multi-junction photovoltaics. Therefore, more effective inter- or transport layers are urgently required. To tackle these recombination losses, we introduce ortho-carborane as an interlayer material that has a spherical molecular structure and a three-dimensional aromaticity. Based on a variety of experimental techniques, we show that ortho-carborane decorated with phenylamino groups effectively passivates the perovskite surface and essentially eliminates the non-radiative recombination loss across the perovskite/C60 interface with high thermal stability. We further demonstrate the potential of carborane as an electron transport material, facilitating electron extraction while blocking holes from the interface. The resulting inverted perovskite solar cells deliver a power conversion efficiency of over 23% with a low non-radiative voltage loss of 110 mV, and retain >97% of the initial efficiency after 400 h of maximum power point tracking. Overall, the designed carborane based interlayer simultaneously enables passivation, electron-transport and hole-blocking and paves the way toward more efficient and stable perovskite solar cells.

Proton tautomerism and stereoisomerism of 4-amino-1,3-thiazol-2(5H)-one derivatives bearing substituents with opposite electronic effects: Synthesis, structure and spectroscopic studies

New compounds of high pharmacological interest: 5-dimethylaminomethylidene-4-phenylamino-1,3-thiazol-2(5H)-one and 5-methoxycarbonylmethylidene-4-phenylamino-1,3-thiazol-2(5H)-one, were synthesized and investigated. Their crystal structure, chemical environment, and intermolecular interactions were studied by X-ray diffraction method and by NMR and FT-IR spectroscopy. The molecular interactions in the crystals were analyzed using Density Functional Theory (DFT), Quantum Theory of Atoms in Molecules (QTAIM), Hirshfeld surfaces, and fingerprint plots, with special emphasis on stereoisomerism and proton tautomerism. Both investigated compounds occur in the solution (DMSO) and in the solid state in the amine tautomeric form. The ylidene substituent with electron-donating effect only could significantly decrease the resonance effect of the carbonylimino group with the phenylamino moiety. In the molecules of both compounds, the phenylamino group has a synperiplanar conformation, and the ylidene substituent has the Z configuration. The theoretical conformational analysis shows that the coplanar arrangement of the thiazolin-2-one and phenyl systems is preferred.

Novel Morpholine-Bearing Quinoline Derivatives as Potential Cholinesterase Inhibitors: The Influence of Amine, Carbon Linkers and Phenylamino Groups.

A series of novel 4-N-phenylaminoquinoline derivatives containing a morpholine group were designed and synthesized, and their anti-cholinesterase activities and ABTS radical-scavenging activities were tested. Among them, compounds 11a, 11g, 11h, 11j, 11l, and 12a had comparable inhibition activities to reference galantamine in AChE. Especially, compound 11g revealed the most potent inhibition on AChE and BChE with IC50 values of 1.94 ± 0.13 μM and 28.37 ± 1.85 μM, respectively. The kinetic analysis demonstrated that both the compounds 11a and 11g acted as mixed-type AChE inhibitors. A further docking comparison between the 11a- and 12a-AChE complexes agreed with the different inhibitory potency observed in experiments. Besides, compounds 11f and 11l showed excellent ABTS radical-scavenging activities, with IC50 values of 9.07 ± 1.34 μM and 6.05 ± 1.17 μM, respectively, which were superior to the control, Trolox (IC50 = 11.03 ± 0.76 μM). It is worth noting that 3-aminoquinoline derivatives 12a–12d exhibited better drug-like properties.

2,6-Bis(phenylamino)-4-(iminophenyl)benzoquinone

The reaction of 2,4-difluoronitrobenzene with an excess of aniline at 175 °C led to the isolation of an unexpected brown quinone substituted with two phenylamino groups and one phenylimino group. This product was easily distinguished from other expected derivatives because it is brown rather than yellow. The UV/Vis has a weak long wavelength absorption at 480–600 nm accounting for the colour.

The reaction of an amino-functionalized DPP with acrolein

An aminophenyl-functionalized diketopyrrolopyrrole (DPP) was designed and synthesized to react with acrolein. The cyclization reaction between acrolein and the aminophenyl group resulted in an increase in fluorescence at 612 nm in the emission spectrum, along with an 18 nm blue-shift from 630 to 612 nm. This phenomenon occurred because the formation of a quinolyl group led to the disturbance of photoinduced electron transfer from the electron-rich amine group to the electron-poor DPP core.

Reactions introducing 4-cyano-5-dicyanomethylene-2-oxo-3-pyrrolin-3-yl group to 4-ethynyl-N,N-dialkylaniline derivatives and characterization of the resulting dyes

Electrophilic reactions of a strong acceptor, 3-chloro-1-butyl-4-cyano-5-dicyanomethylene-2-oxo-3-pyrroline, with 4-ethynylaniline derivatives were investigated. The major products were found to be the cis- or trans-monoadducts of the pyrroline-type acceptor, i.e., 4-(dialkylamino)phenylethene derivatives in which the ethene moiety is substituted by chlorine and 1-butyl-4-cyano-5-dicyanomethylene-2-oxo-3-pyrrolin-3-yl group. Their stereostructures depended on the substituent attached to the ethynyl group on the opposite side of aminophenyl group. The adducts with a chloroethylene linkage were able to convert to the ethynylene derivatives by triethylamine. Among the obtained D-π-A molecules, the cis-compounds respect to the donor and acceptor groups showed the absorption maximum at longer wavelengths compared with the corresponding trans-compound. The calculation results suggested more polarized structures in the cis-forms, resulting in their bathochromic shift of the absorption.

Improved potency of pyridin-2(1H)one derivatives for the treatment of mechanical allodynia.

Mechanical allodynia, a painful sensation caused by innocuous touch, is a major chronic pain symptom, which often remains without an effective treatment. There is thus a need for new anti-allodynic treatments based on new drug classes. We recently synthetized new 3,5-disubstituted pyridin-2(1H)-one derivatives. By substituting the pyridinone at the 3-position by various aryl/heteroaryl moieties and at the 5-position by a phenylamino group, we discovered that some derivatives exhibited a strong anti-allodynic potency in rats. Here, we report that varying the substitution of the pyridinone 5-position, the 3-position being substituted by an indol-4-yl moiety, further improves such anti-allodynic potency. Compared with 2, one of the two most active compounds of the first series, eleven out of nineteen newly synthetized compounds showed higher anti-allodynic potency, with two of them completely preventing mechanical allodynia. In the first series, hit compounds 1 and 2 appeared to be inhibitors of p38α MAPK, a protein kinase known to underlie pain hypersensitivity in animal models. Depending on the substitution at the 5-position, some newly synthetized compounds were also stronger p38α MAPK inhibitors. Surprisingly, though, anti-allodynic effects and p38α MAPK inhibitory potencies were not correlated, suggesting that other biological target(s) is/are involved in the analgesic activity in this series. Altogether, these results confirm that 3,5-disubstituted pyridine-2(1H)-one derivatives are of high interest for the development of new treatment of mechanical allodynia.

The Role of AQ in the Regioselectivity of Strong Alkyl C-O Bond Activation Catalyzed by Pd(OAc)2: A Density Functional Theory Mechanistic Study.

A density functional theory method was employed to investigate the mechanism of C-O bond activation of butanoic acid substrates bearing the 8-aminoquinoline (AQ) group catalyzed by Pd(OAc)2. The whole reaction consists of five fundamental steps: the chelation of substrate A1, the C-H activation step, the C-N coupling step, the protodepalladation step, and the release of the final product. The calculated results indicated that the protodepalladation step is the rate-determining step with a free energy barrier of 24.3 kcal/mol. This theoretical study pointed out that the energy barriers of C-H activation in the presence and absence of AQ are 11.3 and 26.6 kcal/mol, respectively. This is to say that the installation of the AQ directing group is critical to the regioselectivity of C-H activation and the β-O elimination steps, and this reason enables selective activation of the γ C-O bond. Furthermore, this chelating functionality facilitated the protodepalladation step because the energy barrier of the protodepalladation step was decreased with the coordination of the AQ directing group with a Pd center, and that was 39.3 kcal/mol in the absence of AQ. This also explains why no product formation was observed in the experiment upon changing the directing AQ group to a phenylamino group. Finally, other substrates bearing the phenol leaving group at the β- and δ-positions of carbonyl were investigated in order to expand the applicability of the AQ directing strategy. This work could provide new theoretical insights into the activation of strong alkyl C(sp3) covalent bonds via the AQ directing strategy.

Precisely Traceable Drug Delivery of Azoreductase-Responsive Prodrug for Colon Targeting via Multimodal Imaging.

We report the development of an azoreductase-responsive prodrug AP-N═N-Cy in which the precursor compound AP, a readily available podophyllotoxin derivative, is linked with a NIR fluorophore (Cy) via a multifunctional azobenzene group. This type of azo-based prodrug can serve as not only an azoreductase-responsive NIR probe to real-time tracking of the drug delivery process but also a delivery platform for an anticancer compound (AdP). We have shown that cleavage of the multifunctional azobenzene group in AP-N═N-Cy only occurred in the presence of azoreductase, which specifically secretes in the colon, resulting in direct release of AdP through an in situ modification of a phenylamino group on the precursor AP. Moreover, introduction of the azobenzene group endows the prodrug with an unique fluorescence "off-on" property and served as a switch to "turn on" the fluorescence of Cy as consequence of a self-elimination reaction with breakage of an azo bond. Such a prodrug can be administered orally and exhibit high stability and low toxicity before arriving at the colon. In view of the synchronism of drug release and the fluorescence turn-on process, the fluorescence imaging method was utilized to precisely trace drug delivery in vitro, ex vivo, and in vivo. Distinguishingly, the biodistribution of AdP and Cy in various tissues was further precisely mapped at the molecular level using imaging mass spectrometry. To the best of our knowledge, this is the first time that the in vivo real-time precise tracking of the colon-specific drug release and biodistribution was reported via a multimodal imaging method.

Molecular design and application of novel small molecule organic dyes featuring bis(arylvinyl)phenyl amino group for dye-sensitized solar cells

Small molecule organic dyes (SMODs) FWD7 and FWD8 featuring novel donor bis(arylvinyl)phenyl amino (BAPA) were designed for dye-sensitized solar cells (DSSCs). Absorption spectra of FWD7 featuring furanyl groups and FWD8 featuring thiophenyl groups showed about 20 nm bathochromic shifts and obviously bigger molar extinction coefficients (ε) compared with FWD5 featuring phenyl groups. The DSSCs sensitized by FWD7 and FWD8 exhibited good photovoltaic parameters: short-circuit current density (Jsc) 9.88 and 11.59 mA cm−2, open-circuit voltage (Voc) 0.69 and 0.75 V, and power conversion efficiency (η) 4.89% and 6.01%, respectively. The bigger Rrec and τe values of FWD8 (Rrec = 88.53 Ω cm−2 and τe = 10.76 ms) compared with FWD7 (Rrec = 59.06 Ω cm−2 and τe = 6.80 ms) gave a good explanation of the former’s bigger Voc. The results showed that both bis(furanylvinyl)phenyl amino and bis(thiophenylvinyl)phenyl amino groups are good donor groups, while the latter is more efficient.

Grafting of active carbon nanotubes onto carbon fiber using one-pot aryl diazonium reaction for superior interfacial strength in silicone resin composites

Abstract A novel and effective method was proposed for grafting carbon nanotubes (CNTs) with amino groups onto the surface of carbon fibers (CFs) by using one-pot aryl diazonium reaction in mild, eco-friendly conditions. Based on the diazonium reaction, CNTs were grafted with phenyl amino groups, and then functionalized CNTs (CNT-NH2 ) were modified onto the fiber surface to enhance fiber surface roughness and wettability , which could potentially increase interfacial strength of composites. Homogeneous multi-scale structures with different concentrations of CNTs were achieved. Interfacial properties of hybrid composites were closely dependent on the grafting density. The resulting hierarchical reinforcements improved composites interfacial strength significantly by the enhanced mechanical interlocking and the formed chemical bonding at the interface.

Design, synthesis and anticancer activity of trifluoromethylphenylamino substituted spiroindoles

Organofluorines are a group of fluorinated substances with broad application as pharmaceuticals, agrochemicals and polymers. We designed and synthesized a series of new biologically active trifluoromethyl containing indole derivatives. Target 2´-aminoanalogs and 2,2´-diaminoanalogs of 1-methoxyspirobrassinol methyl ether bearing (4-trifluoromethylphenylamino) or 3,5-bis(trifluoromethyl)phenylamino moiety were prepared by spirocyclization methodology. The newly synthesized indole analogs display higher potency of antiproliferative effect against eight human leukemia and solid tumor cell lines than their parental natural phytoalexin. The most potent antiproliferative agents were 2,2´-diaminoanalogs possessing two 3,5-bis(trifluoromethyl)phenylamino groups, which displayed higher potency than cisplatin against screened cancer cell lines, but at the same time lower cytotoxicity than cisplatin on non-malignant murine fibroblasts NIH 3T3.

A non-MPD-type reverse osmosis membrane with enhanced permselectivity for brackish water desalination

A new sulfonated diamine monomer, namely 3,3′-(ethane-1,2-diylbis(azanediyl))bis(2,6-dimethylbenzenesulfonic acid) (EDADMBSA), was designed and synthesized in order to fabricate a novel thin-film composite (TFC) reverse osmosis (RO) membrane by using the interfacial polymerization (IP) technique with trimesoyl chloride (TMC). In particular, EDADMBSA was employed as the sole reactant in the aqueous phase during the IP process, instead of the conventional m-phenylene diamine (MPD). Due to the presence of two methyl groups next to a phenylamino group that could exert a strong steric hindrance influence, the rotation of the polyamide main chain was significantly enforced, as clearly illustrated by a molecular dynamics simulation. In this manner, sufficient free volumes were generated in the polymer matrix, allowing for a lower water penetration resistance. The optimal pure water permeability (PWP) attained with this EDADMBSA/TMC membrane was as high as 1.9 ± 0.2 L m−2 h−1 bar−1, which is 2.6–2.7 times greater than that of a self-made MPD/TMC membrane under the same test conditions. Furthermore, the unique methyl substituents could also serve as void occupiers, allowing the TFC membrane to retain a reasonably high water-solute selectivity. Compared to commercial BW30FR (Dow Chemical), the novel membrane displayed a superior ability to reject all the ions in a simulated desalination test, revealing its promising potential as a separation medium for brackish water desalination.

Probing Charge-Transfer and Short-Lived Triplet States of a Biosensitive Molecule, 2,6-ANS: Transient Absorption and Time-Resolved Spectroscopy.

We report the existence of a short-lived triplet electronic state of 2,6-ANS (2-anilinonaphthalene-6-sulfonic acid), which, together with nonplanar (NP) and planar [charge-transfer (CT)] states, is produced following photoexcitation; these results are based on nanosecond transient absorption and time-resolved decays. The short-lived triplet state has a lifetime of ∼126 ns and is observed via triplet–triplet (T–T) transitions after exciting 2,6-ANS with a pump laser pulse of 355 nm (probe wavelength range of 360–500 nm). Moreover, the CT state, which is very close to the NP state produced from the locally excited state/NP state, emits active fluorescence with a lifetime of ∼11 ns. The solvent plays a major role in the rotation of the phenylamino group during the conversion of the NP state to the CT state, and vice versa. Intersystem crossing occurs from the CT state. Thus, investigating the triplet state together with the CT/NP states of 2,6-ANS, a commonly used probe for sensing proteins and other biomolecules, is highly relevant and helps reveal its photoexcitation dynamics.

Excited-state proton transfer induced [4 + 2] and [4 + 4] photocycloaddition reactions of an oxazoline: Mechanism and selectivity

[4+4] and [4+2] photocycloadditions have not computationally attracted the same level of attention as [2+2] photocycloadditions. Herein we have employed density-functional theory (DFT), complete active-space self-consistent field (CASSCF), and its multi-state second-order perturbation theory (MS-CASPT2) methods to systematically explore excited-state intramolecular proton transfer (ESIPT) induced [4+4] and [4+2] photocycloaddition mechanisms of an oxazoline. On the basis of the results, we have found that the ESIPTs in the S1 state are not as efficient as those in the T1 state concerning experimentally used irradiation wavelength. Instead, the T1 ESIPTs generate two sets of endo and exo precursors of [4+4] and [4+2] photocycloadditions. In these reactions, the C atom of the furan group and the N atom of the aminophenyl group are first bonded leading to a diradical intermediate. This reaction step has a small barrier and is thermodynamically favorable. However, the remaining CC bond formation is blocked in the T1 state due to its huge reaction barrier. Therefore, the system hops to the S0 state via T1→S0 intersystem crossings at T1/S0 crossing points. These nonadiabatic processes are efficient because of structural and energetic similarities of T1/S0 crossing points with their nearby T1 intermediates. In the S0 state, the CC bond formation becomes a barrierless process. Finally, we have discussed possible origins for high regioselectivity and enantioselectivity of these photocycloaddition reactions.