P-substituted Phenyl Research Articles

Synthesis and photooxygenation of 3-(p-substituted phenyl)-3a,8a-dihydro-4H-cyclohepta[d]isoxazoles: facial selectivity.

Two 3-(p-substituted phenyl)-3a,8a-dihydro-4H-cyclohepta[d]isoxazoles were synthesized by 1,3-dipolar cycloaddition of the corresponding nitrile oxides with cycloheptatriene. Two endoperoxides were synthesized as facially selective and single products in high yields (93%-95%) from the reactions of isoxazole derivatives with singlet oxygen. The exact configurations of the endoperoxide with a methyl group in the phenyl ring and the diol synthesized from it were confirmed by X-ray analysis. To elucidate the mechanism, the formation energy of the endoperoxide was investigated by simulations using the software package Gaussian 09 and density functional theory calculations via the M06-2X/6-311+G(d,p) level method in dichloromethane. The results were consistent with experimental findings showing the formation of isoxazole products.

Organic Donor-Acceptor Thermally Activated Delayed Fluorescence Photocatalysts in the Photoinduced Dehalogenation of Aryl Halides.

We report a family of donor-acceptor thermally activated delayed fluorescent (TADF) compounds based on derivatives of DMAC-TRZ, that are strongly photoreducing. Both Eox and thus E*ox could be tuned via substitution of the DMAC donor with a Hammett series of p-substituted phenyl moieties while Ered remained effectively constant. These compounds were assessed in the photoinduced dehalogenation of aryl halides, and analogues bearing electron withdrawing groups were found to produce the highest yields. Substrates of up to Ered=-2.72 V could be dehalogenated at low PC loading (1 mol %) and under air, conditions much milder than previously reported for this reaction. Spectroscopic and chemical studies demonstrate that all PCs, including literature reference PCs, photodegrade, and that it is these photodegradation products that are responsible for the reactivity.

Exploring BenzylethoxyAryl Urea Scaffolds for Multitarget Immunomodulation Therapies.

Thirteen benzylethoxyaryl ureas have been synthesized and biologically evaluated as multitarget inhibitors of VEGFR-2 and PD-L1 proteins to overcome resistance phenomena offered by cancer. The antiproliferative activity of these molecules on several tumor cell lines (HT-29 and A549), on the endothelial cell line HMEC-1, on immune cells (Jurkat T) and on the non-tumor cell line HEK-293 has been determined. Selective indexes (SI) have been also determined and compounds bearing p-substituted phenyl urea unit together with a diaryl carbamate exhibited high SI values. Further studies on these selected compounds to determine their potential as small molecule immune potentiators (SMIPs) and as antitumor agents have been performed. From these studies, we have concluded that the designed ureas have good tumor antiangiogenic properties, exhibit good inhibition of CD11b expression, and regulate pathways involved in CD8 T-cell activity. These properties suggest that these compounds could be potentially useful in the development of new cancer immune treatments.

Substituent and Surfactant Effects on the Photochemical Reaction of Some Aryl Benzoates in Micellar Green Environment.

In this study, we carried out preparative and mechanistic studies on the photochemical reaction of a series of p-substituted phenyl benzoates in confined and sustainable micellar environment. The aim of this work is mainly focused to show whether the nature of the surfactant (ionic or nonionic) leads to noticeable selectivity in the photoproduct formation and whether the electronic effects of the substituents affect the chemical yields and the rate of formation of the 5-substituted-2-hydroxybenzophenone derivatives. Application of the Hammett linear free energy relationship (LFER) on the rate of formation of benzophenone derivatives, on the lower energy band of the UV-visible absorption spectra of the aryl benzoates and 5-substituted-2-hydroxybenzophenone derivatives allows a satisfactory quantification of the substituent effects. Furthermore, UV-visible and 2D-NMR (NOESY) spectroscopies have been employed to measure the binding constant Kb and the location of the aryl benzoates within the hydrophobic core of the micelle. Finally, TD-DFT calculations have been carried out to estimate the energies of the absorption bands of p-substituted phenyl benzoates and 5-substituted-2-hydroxybenzophenone derivatives providing good linear correlation with those values measured experimentally.

Characterisation of twelve newly synthesised N-(substituted phenyl)-2-chloroacetamides with QSAR analysis and antimicrobial activity tests.

In this study we screened twelve newly synthesised N-(substituted phenyl)-2-chloroacetamides for antimicrobial potential relying on quantitative structure-activity relationship (QSAR) analysis based on the available cheminformatics prediction models (Molinspiration, SwissADME, PreADMET, and PkcSM) and verified it through standard antimicrobial testing against Escherichia coli, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Candida albicans. Our compounds met all the screening criteria of Lipinski’s rule of five (Ro5) as well as Veber’s and Egan’s methods for predicting biological activity. In antimicrobial activity tests, all chloroacetamides were effective against Gram-positive S. aureus and MRSA, less effective against the Gram-negative E. coli, and moderately effective against the yeast C. albicans. Our study confirmed that the biological activity of chloroacetamides varied with the position of substituents bound to the phenyl ring, which explains why some molecules were more effective against Gram-negative than Gram-positive bacteria or C. albicans. Bearing the halogenated p-substituted phenyl ring, N-(4-chlorophenyl), N-(4-fluorophenyl), and N-(3-bromophenyl) chloroacetamides were among the most active thanks to high lipophilicity, which allows them to pass rapidly through the phospholipid bilayer of the cell membrane. They are the most promising compounds for further investigation, particularly against Gram-positive bacteria and pathogenic yeasts.

Discovery of 4-alkoxy-2-aryl-6,7-dimethoxyquinolines as a new class of topoisomerase I inhibitors endowed with potent invitro anticancer activity.

In our attempt to develop potential anticancer agents targeting Topoisomerase I (TOP1), two novel series of 4-alkoxy-2-arylquinolines 14a-p and 19a-c were designed and synthesized based on structure activity relationships of the reported TOP1 inhibitors and structural features required for stabilization of TOP1-DNA cleavage complexes (TOP1ccs). The invitro anticancer activity of these two series of compounds was evaluated at one dose level using NCI-60 cancer cell lines panel. Compounds 14e-h and 14m-p, with p-substituted phenyl at C2 and propyl linker at C4, were the most potent and were selected for assay at five doses level in which they exhibited potent anticancer activity at sub-micromolar level against diverse cancer cell lines. Compound 14m was the most potent with full panel GI50 MG-MID 1.26μM and the most sensitive cancers were colon cancer, leukemia and melanoma with GI50 MG-MID 0.875, 0.904 and 0.926μM, respectively. Melanoma (LOX IMVI) was the most sensitive cell line to all tested compounds displaying GI50 from 0.116 to 0.227μM, TGI from 0.275 to 0.592μM and LC50 at sub-micromolar concentration against almost of the tested compounds. Compounds 14e-h and 14m-p were assayed using TOP1-mediated DNA cleavage assay to evaluate their ability to stabilize TOP1ccs resulting in cancer cell death. The morpholino analogs 14h and 14p exhibited moderate TOP1 inhibitory activity compared to 1μM camptothecin suggesting their use as lead compounds that can be optimized for the development of more potent anticancer agents with potential TOP1 inhibitory activity. Finally, Swiss ADME online web tool predicted that compounds 14h and 14p possessed good oral bioavailability and druglikeness characteristics.

Bazı Yeni Benzoksazol Türevlerinin Sentezi ve Antimikrobiyal ve Sitotoksik Aktivite Çalışmaları

There is an urgent need to develop new antimicrobial drugs due to the rapid development of resistance to increasing microbial infectious diseases and drugs used in their treatment. Also, the compounds synthesized for use in cancer treatment limit their use due to their cytotoxic effect on normal cells and cancerous cells, and their side effects are high. For this reason, researches continue to intensify the drugs developed for cancer treatment to be selectively effective on cancer cells and to reduce their side effects as much as possible. Within this study's scope, 7 compounds of 2-(p-substituted phenyl)-5-(2-substitutedacetamido) were synthesized in 3 steps, 2 of which were original, and their structures were illuminated by HRMS, 1H-NMR, and 13C-NMR spectroscopy methods. Antimicrobial effects on 10 different microorganisms were evaluated. In addition, cytotoxic activities were investigated on MCF-7 and A549 cell lines by the MTT method. As a result of the study, it was determined that the synthesized compounds were both antibacterial and antifungal at MIC values ranging from 64-256 µg/mL, and compound 7 had significant cytotoxic activity on both A549 and MCF-7. The results obtained will make an important contribution to the studies conducted to develop new or alternative antimicrobial and cytotoxic agents.

Synthesis, antiproliferative and antitrypanosomal activities, and DNA binding of novel 6-amidino-2-arylbenzothiazoles

A series of 6-amidinobenzothiazoles, linked via phenoxymethylene or directly to the 1,2,3-triazole ring with a p-substituted phenyl or benzyl moiety, were synthesised and evaluated in vitro against four human tumour cell lines and the protozoan parasite Trypanosoma brucei. The influence of the type of amidino substituent and phenoxymethylene linker on antiproliferative and antitrypanosomal activities was observed, showing that the imidazoline moiety had a major impact on both activities. Benzothiazole imidazoline 14a, which was directly connected to N-1-phenyl-1,2,3-triazole, had the most potent growth-inhibitory effect (IC50 = 0.25 µM) on colorectal adenocarcinoma (SW620), while benzothiazole imidazoline 11b, containing a phenoxymethylene linker, exhibited the best antitrypanosomal potency (IC90 = 0.12 µM). DNA binding assays showed a non-covalent interaction of 6-amidinobenzothiazole ligands, indicating both minor groove binding and intercalation modes of DNA interaction. Our findings encourage further development of novel structurally related 6-amidino-2-arylbenzothiazoles to obtain more selective anticancer and anti-HAT agents.

Experimental and quantum chemical studies of the structural and spectral properties of novel diazenyl formazans

A new series of 3-(p-substitutedphenyl)-5-phenyl-1-(4-phenyldiazenyl)phenylformazans were synthesized by coupling p-substituted phenyl or pyridinylhydrazones with p-aminoazobenzene diazonium chloride. All compounds were characterized by FT-IR, UV–Vis, 1H NMR, and 13C NMR spectroscopic techniques, and HR-MS. DFT was used to calculate the molecular structures and 1H and 13C chemical shift values of the synthesized compounds with PBE1PBE functional and 6-311G(2d,2p) basis set combination. The IR spectra of the novel formazans were calculated using DFT at PBE1PBE/6-311G(d,p) level of theory. The electronic absorption spectra of the optimized structures were evaluated by TD-DFT method at PBE1PBE/6-311G(2d,2p) level of theory. The absorption spectra of the synthesized diazenyl formazans were investigated in three different solvents. A good correlation was established between the experimental data and calculated results.

Experimental and theoretical study of the structure, frontier molecular orbital, tautomerism and spectral analysis of 3-(p-substituted phenyl)-5-phenyl-1H-pyrazole

This paper demonstrates the structural and spectral characteristics of conjugated pyrazoles 3-(p-N,N dimethyl aminophenyl)-5-phenyl-1H-pyrazole (DAPP) and 3-(p-nitrophenyl)-5-phenyl-1H-pyrazole (NPP), with particular attention to the influence of functional group on their tautomeric behaviour and energy band gaps. The HOMO-LUMO transitions, frontier molecular orbitals, dipole moment, and electron charges distribution were computed using density functional theory (DFT) for each tautomer. The absorption and transmission spectra were experimentally obtained under certain solutions and concentration. The results showed that functional groups play a significant role in the formation of tautomers. Further, the energy gap for NPP was calculated experimentally and found to be 3.79 eV. The energy gap was increased substantially by replacing nitro group with N,N-dimethylamino group (DAPP) to be 3.99 eV. The theoretical calculations results were completely agreed with the experimental data, and proved for the first time, proton transfer from nitrogen to carbon with loss of aromaticity in pyrazole dye.

Magnetic covalent hybrid of graphitic carbon nitride and graphene oxide as an efficient catalyst support for immobilization of Pd nanoparticles

For the first time a magnetic carbon based hybrid catalyst, Pd@g-C3N4-Fe-GO, is prepared through covalent conjugation of magnetic graphitic carbon nitride and graphene oxide followed by incorporation of Pd nanoparticles. First, the formation of the catalyst was confirmed via XRD, TG, BET, TEM, FTIR, ICP and VSM analyses and then its catalytic activity for promoting Suzuki and Sonogashira coupling reactions under mild reaction condition was investigated. To elucidate whether hybridization of two carbon materials could improve the catalytic activity, the catalytic activity of the catalyst was compared with the control catalysts (Pd@g-C3N4 -GO, Pd@g-C3N4-Fe, Pd@ Fe-GO, Pd@g-C3N4, Pd@GO and the GO/g-C3N4 physical hybrid). Moreover, the role of magnetic nanoparticles in the catalytic performance was confirmed. Notably, the catalytic activities of the catalyst and the control sample prepared via physical hybridization of two carbon materials were compared to confirm the effect of covalent conjugation on the catalytic activity. Moreover, the study of the substituent effect of p-substituted phenyl iodides was considered by Hammett plot, which revealed a beneficial effect of electron-withdrawing side groups for the CC coupling reaction. Finally, the recyclability of Pd@g-C3N4-Fe-GO as well as leaching of Pd and magnetic nanoparticles was studied.

Bis-heterocycles. Part I: tetrahydro-5,5′- bi(1,2,4-triazin-6-ones)

Abstract Selected sets of tetrahydro-5,5′-bi(1,2,4-triazines) (1–3) appended with acetyl, benzoyl, and ester moieties at C-3 position and N-1 (p-substituted)phenyl ring have been prepared and characterized by spectral (IR, NMR, MS) data and X-ray diffraction for compound 3a. Their synthesis was achieved in high yield via the reaction of diethyl aminomalonate with various N-(aryl)hydrazonoyl chlorides in the presence of triethylamine.

Fluorescent and Electroactive Monoalkyl BTD-Based Liquid Crystals with Tunable Self-Assembling and Electronic Properties

We report here on a series of redox active benzothiadiazole-based luminophores functionalized on one edge with a phenyl-nonyl substituent, which confers these molecules a rodlike shape and a tendency to self-assemble into layered superstructures. On the other edge, the molecules are endowed with different p-substituted phenyl rings, which allows the modulation of their redox and optical properties on the basis of the electronic nature of the terminal substituents. We have found that just one lateral alkyl chain is sufficient to induce mesomorphism in these molecules, which present nematic or smectic mesophases upon thermal treatment. Single-crystal analysis allows us to get an insight into the nature of the forces responsible for different supramolecular assemblies in these derivatives, and point to a strong contribution of the terminal groups in the different arrangements observed. The interesting redox and optical properties together with their self-assembling tendencies render these new materials interesting candidates for optoelectronics.

Two hydrazones derived from 1-aryl-3-(p-substituted phenyl)prop-2-en-1-one: synthesis, crystal structure, Hirshfeld surface analysis and in vitro biological properties.

Two chalcones were synthesized by the aldolic condensation of enolizable aromatic ketones with substituted benzaldehydes under Claisen-Schmidt reaction conditions and then treated with 2,4-dinitrophenylhydrazine to yield their corresponding hydrazones. The two (E,Z)-2,4-dinitrophenylhydrazone structures, namely (Z)-1-(2,4-dinitrophenyl)-2-[(E)-3-(4-methylphenyl)-1-phenylallylidene]hydrazine, C22H18N4O4, (H1), and (Z)-1-[(E)-3-(4-chlorophenyl)-1-(naphthalen-1-yl)allylidene]-2-(2,4-dinitrophenyl)hydrazine, C25H17ClN4O4, (H2), were isolated by recrystallization and characterized by FT-IR, UV-Vis, single-crystal and powder X-ray diffraction methods. The UV-Vis spectra of the hydrazones have been studied in two organic solvents of different polarity. It was found that (H2) has a molar extinction coefficient larger than 40000. Single-crystal X-ray diffraction analysis reveals that the molecular zigzag chains of (H1) and (H2) are interconnected through noncovalent contacts. A quantitative analysis of the intermolecular interactions in the crystal structures has been performed using Hirshfeld surface analysis. All the synthesized chalcones and hydrazones were evaluated for their antibacterial and antioxidant activities. Results indicate that the studied compounds show significant activity against Gram negative Escherichia coli strain and the chalcone 3-(4-methylphenyl)-1-phenylprop-2-en-1-one, (C1), was the most effective. In addition, only hydrazone (H1) displayed a moderate DPPH (2,2-diphenyl-1-picryl hydrazyl) scavenging efficiency.

Discovery of Oxime Ethers as Hepatitis B Virus (HBV) Inhibitors by Docking, Screening and In Vitro Investigation.

A series of oxime ethers with C6-C4 fragment was designed and virtually bioactively screened by docking with a target, then provided by a Friedel–Crafts reaction, esterification (or amidation), and oximation from p-substituted phenyl derivatives (Methylbenzene, Methoxybenzene, Chlorobenzene). Anti-hepatitis B virus (HBV) activities of all synthesized compounds were evaluated with HepG2.2.15 cells in vitro. Results showed that most of compounds exhibited low cytotoxicity on HepG2.2.15 cells and significant inhibition on the secretion of HBsAg and HBeAg. Among them, compound 5c-1 showed the most potent activity on inhibiting HBsAg secretion (IC50 = 39.93 μM, SI = 28.51). Results of the bioactive screening showed that stronger the compounds bound to target human leukocyte antigen A protein in docking, the more active they were in anti-HBV activities in vitro.

Site selective [bmIm]OH catalyzed C[sbnd]C bond functionalization under green conditions

Effective methodology that activates selectively either end of a carbon–carbon triple bond requires key challenge of differentiating between the multitude of CC bonds present in complex organic molecule. The synthetic strategy exploited the electronic biases within the substrate and successfully achieved site–selective [bmIm]OH catalyzed CC bond functionalization under mild reaction conditions. This resulted in C-2-selective addition of phenacyl bromide on p-substituted phenyl acetylene and C-1 selective addition on the o-substituted phenyl acetylene leading to CC bond formation. The reaction proceeded smoothly with excellent yield under ambient conditions. This report demonstrates the progress on the catalytic activity of recyclable [bmIm]OH for selective CC bond formation.

Panchromatic Photosensitizers Based on Push-Pull, Unsymmetrically Substituted Porphyrazines.

A series of five push-pull porphyrazines of A3 B type, in which unit B is an isoindole 4-carboxylic acid, has been prepared. The units A have been endowed with thioether, amine, ether and alkyl functions, either directly attached to the β-position of the pyrrolic units, or connected to the porphyrazine core through p-substituted phenyl groups. Attaching the electron-donor functions to the porphyrazine periphery produces strong perturbations in the electronic and redox properties of the dyes. Their HOMO and LUMO energies, estimated from the optical and redox data, as well as with DFT calculations, raise upon functionalization with amines, while the corresponding frontier orbital energetic levels lower upon functionalization with thioethers, p-methoxyphenyl or p-tert-butylphenyl groups. The effective interaction of peripheral substitution with the macrocycle produces chromophores with panchromatic absorption between 300 and 750-850 nm.

Synthesis and <i>in vitro</i> antiprotozoal activity of some 2- amino-4-phenyloxazole derivatives

Purpose: To prepare some 2-amino-4-(p-substituted phenyl)-oxazole derivatives and to evaluate their in vitro antiprotozoal activity against Giardia lamblia and Trichomonas vaginalis.Methods: The 2-amino-4-(p-substituted phenyl)-oxazoles (a-g) were synthesized by microwave (MW) irradiation of mixtures of p-substituted 2-bromoacetophenones and urea in dimethylformamide (DMF). All compounds were identified by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy and lowand high-resolution mass spectrometry (HRMS). NMR assignments were made based on heteronuclear single quantum coherence (HSQC) and heteronuclear multiple bond correlation (HMBC) experiments. Each synthesized compound’s melting point was determined. Antiprotozoal activity against Giardia intestinalis and Trichomonas vaginalis was quantified using a rigorous and sensitive subculture method. The commercial drug, metronidazole, was used as positive control. The 50 % inhibitory concentration (IC50) of the antiprotozoal agents for each protozoa was determined.Results: Seven 2-amino-4-(p-substituted phenyl)-oxazoles (a-g) were synthesized. The most active compounds against G. lamblia was 2-amino-4-(p-benzoyloxyphenyl)-oxazole (3d) with an IC50 of 1.17 μM, while compound 3e (2-amino-4-(p-bromophenyl)-oxazole) showed the highest anti-trichomonal activity (IC50, 1.89 μM).Conclusion: The in vitro antigiardial activity of 2-amino-4-(p-benzoyloxyphenyl) oxazole was higher than that exhibited by metronidazole; however, it is necessary increase the number of synthetic derivatives in order to be able to determine their structure-activity relationship.Keywords: Antiprotozoal, 2-Amino-4-phenyl-oxazoles, Giardia lamblia, Trichomonas vaginalis

The nuclear orphan receptor NR4A1 regulates β1‐integrin expression in pancreatic and colon cancer cells and can be targeted by NR4A1 antagonists

β1-Integrin is highly expressed and is a negative prognostic factor for colon and pancreatic cancer patients and the gene plays a functional role in cell migration and invasion. In this study, we demonstrate that β1-integrin expression is regulated in pancreatic and colon cancer cells by the pro-oncogenic orphan nuclear receptor 4A1 (NR4A1, Nur77, TR3) and knockdown of this receptor by RNA interference decreases β1-integrin protein and mRNA expression, α5-integrin, and also expression of β1-integrin-dependent phosphorylation of FAK (pFak). Knockdown of NR4A1 also decreased migration and fibronectin-induced adhesion in pancreatic (Panc1, L3.6 pL, and MiaPaCa2) and colon (RKO and SW480) cancer cells. 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methane (C-DIM) compounds containing p-hydroxy (DIM-C-pPhOH) and p-carbomethoxy (DIM-C-pPhCO2 Me) groups are NR4A1 ligands that act as antagonists for this receptor. Treatment of pancreatic and colon cancer cells with DIM-C-pPhOH or DIM-C-pPhCO2 Me mimics the effects of NR4A1 knockdown and decreases β1-integrin expression, β1-integrin regulated genes and responses including migration and adhesion. The results demonstrate a novel method for targeting β1-integrin in colon and pancreatic cancer cells and indicate possible clinical applications for C-DIM/NR4A1 antagonists for pancreatic and colon cancer therapy.

Syntheses of non-aromatic medium and large rings synthesized via phenylnitrenium ions

We describe the preparation of m- and p-substituted phenyl azides which, on treatment with trifluoromethanesulfonic acid in chloroform (and only in one case, after adding trifluoroacetic acid) at 0°C, gives rise to the intermediate phenylnitrenium ions that undergo intramolecular cyclization to give six-, eight-membered carbocycles, and ten-membered heterocycles. Intramolecular cyclization of 1-(4-azidophenyl)-4-phenylbutane (3b) gives direct access to the 1,2,3,4-tetrahydronaphthalene lignan scaffold with a good yield. When the same reaction is carried out on 1-(3-azidophenyl)-4-phenylbutane (3a), the meta isomer of 3b, the 3-aminodibenzo[a,c]cyclooctadiene is obtained with a modest yield. When an ethoxycarbonyl group is introduced at position two of the butene chain [16a, as an E/Z mixture (1/4)], the ethyl 3-aminobenzo[a,c]octatriene carboxylate was the major compound, and the 10-membered heterocycle the minor one, both derived from (E)-16a. Finally, when a methyl group is located at the para position of the azido group [(E)-16b], cyclization involves the carbon atom ortho to the nitrogen atom and the ethyl 4-methyl-1-tosylaminobenzo[a,c]octatriene carboxylate is the only compound obtained, after treatment with tosyl chloride. With all these structural changes, we have switched over from the formation of mixtures of compounds to the regioselective formation of the target molecule, suggesting the corresponding mechanism of reaction and expanding the knowledge of this type of reaction.