Phenyl Derivatives Research Articles

Synthesis, Structural Analysis, and Biological Evaluation of Novel ((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl Derivatives

The objective of this study was to evaluate the synthesis, structural analysis, and biological effects of novel ((2, 4-dioxothiazolidin-5-ylidene)methyl)phenyl derivatives. The efficacy of 15-PGDH inhibition increased for the substituents in the derivatives in the order: cyclohexylpropyl > cyclohexylethyl > cyclohexylmethyl > cyclohexyl. Compound 12 inhibited 15-PGDH activity by binding to the amino acids Ile 214, Ile 210, Ile 194, Gln 148, and Leu 191 of 15-PGDH. Compounds 4, 22, and 23 produced the highest increment in PGE2 concentration, which was 122.19, 100.14, and 206.80%, respectively, compared to that of the control. Also, compounds 38 and 39, in which the central phenyl ring and the 2, 4-thiazolidinedione moiety were linked by a single bond, produced a relatively high increment in PGE2 concentration, which was 106.81 and 118.66%, respectively, compared to that of the control. The wound closure rates of compounds 22 and 39 were the highest, being 247.56 and 202.42%, respectively, compared to that of the positive control. Therefore, compounds 22 and 39 could not only efficiently regulate PGE2 concentration, but also induce cellular regeneration, and are expected to effectively treat a variety of diseases resulting from PGE2 deficiency.

Structure-activity relationship and cardiac safety of 2-aryl-2-(pyridin-2-yl)acetamides as a new class of broad-spectrum anticonvulsants derived from Disopyramide.

A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly active in the 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6Hz and kindling models of pharmacoresistant seizures. Furthermore, the compounds showed good therapeutic indices between anticonvulsant activity and motor impairment. Structure-activity relationship (SAR) trends clearly showed the highest activity resides in unsubstituted phenyl derivatives or compounds having ortho- and meta- substituents on the phenyl ring. The 2-aryl-2-(pyridin-2-yl)acetamides were derived by redesign of the cardiotoxic sodium channel blocker Disopyramide (DISO). Our results show that the compounds preserve the capability of the parent compound to inhibit voltage gated sodium currents in patch-clamp experiments; however, in contrast to DISO, a representative compound from the series 1 displays high levels of cardiac safety in a panel of in vitro and in vivo experiments.

Design, Synthesis, Molecular Modeling and Anti-HIV Assay of Novel Quinazolinone Incorporated Coumarin Derivatives.

The emergence of drug-resistant viral strains has created the need for the development of novel anti-HIV agents with a diverse structure that targets key enzymes in the HIV lifecycle. Considering the pharmacophore of integrase inhibitors, one of the validated targets for anti-HIV therapy, we designed a quinazolinone incorporated coumarin scaffold to affect HIV. Coumarin is a beta enol ester and also a well-known drug scaffold. Designed structures were prepared using a one-pot three-component reaction from 3-amino-4-hydroxycoumarin, isatoic anhydride and benzaldehyde derivatives. In vitro anti-HIV and cytotoxicity assay indicated that more than half of the compounds had EC50 values lower than 50 µM. Unsubstituted phenyl derivative showed the highest activity and selectivity with an EC50 value of 5 µM and a therapeutic index of 7. Compounds were docked into the integrase active site to investigate the probable mechanism of action. Accordingly, the hydroxyl moiety of coumarin along with the carbonyl of the quinazolinone ring could function as the metal chelating group. Quinazolinone and phenyl groups interact with side chains of IN residues, as well. Here, a novel anti-HIV scaffold is represented for further modification and in-vivo studies.

Novel noscapine derivatives stabilize the native state of insulin against fibrillation

Protein aggregation to form amyloid is associated with many human diseases, increasing the need to develop inhibitors of this process. Here we evaluate the ability of derivatives of the small organic compound noscapine, derived from the opium poppy, to inhibit fibrillation of the model protein insulin. We combined biophysical methods to assess insulin stability and aggregation with computational docking and cell viability studies to identify the most potent derivatives. The best aggregation inhibitor (a phenyl derivative of N-nornoscapine) also demonstrated the highest ability to stabilize native insulin against thermal denaturation. This compound maintained insulin largely in the monomeric and natively folded state under fibrillation conditions and also decreased insulin aggregate toxicity against human neuroblastoma SH-SY5Y cells. The inhibitory effects were specific for insulin fibrillation, as the noscapine compounds did not inhibit fibrillation of other proteins such as α-synuclein, Aβ, and FapC. Our data demonstrate that compounds which stabilize the folded native state of a protein can not only inhibit fibrillation but also decrease the toxicity of the mature fibrillar aggregates of insulin protein.

Anisotropic and magnetic properties in non-metal and non-radical organic aggregates of tri-substituted phenyl derivatives

A new series of tri-substituted phenyl derivatives containing an aromatic imine unit and biphenyl ester possessing various numbers of carbon atoms at the terminal alkoxy chain, OCnH2n+1(n= 7–12), along with a lateralo-ethoxy substituent.

The synthesis of heterocyclic derivatives of phenyl(benzoyl) thiourea

The synthesis of heterocyclic derivatives of phenyl(benzoyl) thiourea

Synthesis of New Derivatives Benzo[4′,5′]imidazo[2′,1′:6,1]pyrido[2,3-d]pyrimidine

The reactions of 4-methyl- and (RS)-4,6-dimethyl-2-phenyl-5,6-dihydrobenzo[4′,5′]imidazo-[2′,1′:6,1]pyrido[2,3-d]pyrimidines and 4-methyl-5,6-dihydrobenzo[4′,5′]imidazo[2′,1:6,l]pyrido[2,3-d]pyrimi-din-2-ol with aromatic and heterocyclic aldehydes under various experimental conditions were studied. It was shown that the reaction with aldehydes upon boiling in acetic anhydride involves exclusively the 6-methylene group in the a-position to the benzimidazole fragment of the tetracycle and is accompanied by a 1,3-prototropic shift, which results in the formation of 6-aryl(hetaryl)methyl-4-methyl derivatives. The 4-methyl group in the substituted 2-phenyl(hydroxy)derivatives of 5,6-dihydrobenzo[4′,5′]imidazo[2′,1′:6,1]pyrido[2,3-d]pyrimidines reacts with aldehydes only under fusion conditions in the presence of ZnCl2. The structure of the synthesized compounds was confirmed by one- and two-dimensional (NOESY) 1H NMR spectroscopy and XRD analysis.

Mixed Carboxyl and Hydrophobic Dendrimer Surface Inhibits Amyloid-β Fibrillation: New Insight from the Generation Number Effect.

Fibrillation of amyloid-β peptide (Aβ) is closely associated with the progression of Alzheimer's disease (AD), and so inhibition of Aβ fibrillation has been considered as one of the promising strategies for AD prevention and treatment. Our group has proposed the hydrophobic binding-electrostatic repulsion (HyBER) theory on inhibiting Aβ fibrillation by a surface with mixed negative charges and hydrophobic groups, which provides a new strategy for the design of potent amyloid inhibitors. Carboxyl-terminated polyamidoamine dendrimer (PAMAM) is a kind of biocompatible nanomaterial with only carboxyl groups on its surface, and its architecture and property vary with the generation number, low-generation dendrimers possessing sparse distributions of terminal groups while high-generation dendrimers having compact surface groups, which offer abundant base materials for further study of the HyBER theory. We have designed a potent amyloid inhibitor with generation 5 PAMAM. To provide new insights into the HyBER mechanism, we have herein proposed to synthesize phenyl-modified PAMAM dendrimers of generations 3 to 6 (G3-P to G6-P) and study the effect of the generation number on Aβ fibrillation. Results show that phenyl derivatives of low-generation dendrimers (G3-P and G4-P) do not show any interference with Aβ aggregation, whereas the phenyl derivatives of high-generation dendrimers (G5-P and G6-P) significantly inhibit Aβ42 aggregation and alter the ultrastructure of Aβ42 aggregates. The results indicate that the density and distribution of surface functional groups on a dendrimer is of great importance for the HyBER effect to happen. The new understanding on the HyBER mechanism would benefit in the development of potent amyloid inhibitors based on the theory.

In Silico Design, Synthesis, and Characterization of Ibuprofen Derivative as Potential Antitumor Agent.

Background: Numerous animal studies and clinical trials in cancer have shown that ibuprofen reduces the incidence of and mortality from cancer. Synthesis of novel conjugate of ibuprofen with the 2-phenyl amino pyrimidine derivative (to mimic small molecules kinase inhibitor anticancers) exhibits significant increase, as compared to free ibuprofen, potential to inhibit proliferation of cancer cells. Methods: The docking study was performed with GOLD software supplied by the Cambridge Crystallographic Data Centre. Thereafter, the chemical synthesis was established. The chemical structures of this study was confirmed by spectral instrumentation; infrared, differential scanning calorimeter thermal analyzer, proton and carbon-13 nuclear magnetic resonance. Results and Discussions: The docking process was successfully conducted and the chemical synthesis yielded a good per cent. The spectral interpretations show characteristic identification of the target chemical compound.

Developing 9,10-anthracene Derivatives: Optical, Electrochemical, Thermal, and Electrical Characterization.

Anthracene-based semiconductors are a class of molecules that have attracted interest due to their air stability, planarity, potential for strong intermolecular interactions, and favorable frontier molecular orbital energy levels. In this study seven novel 9,10-anthracene-based molecules were synthesized and their optical, electrochemical, and thermal properties were characterized, along with their single crystal arrangement. We found that functionalization of the 9,10-positions with different phenyl derivatives resulted in negligible variation in the optical properties with minor (±0.10 eV) changes in electrochemical behavior, while the choice of phenyl derivative greatly affected the thermal stability (Td > 258 °C). Preliminary organic thin film transistors (OTFTs) were fabricated and characterized using the 9,10-anthracene-based molecules as the semiconductor layer. These findings suggest that functionalization of the 9,10-position of anthracene leads to an effective handle for tuning of the thermal stability, while having little to no effect on the optical properties and the solid-state arrangement

Design, Synthesis and Anticancer Evaluation of New Substituted Thiophene-Quinoline Derivatives

A series of new isoxazolyl, triazolyl and phenyl based 3-thiophen-2-yl-quinoline derivatives were synthesized adopting click chemistry approach. In addition, the synthesis of new useful synthon, (2-chloroquinolin-3-yl) (thiophen-2-yl) methanol, is reported. The obtained compounds were characterized by spectral data analysis and evaluated for their anticancer activity. All the derivatives were subjected to in vitro MTT cytotoxicity screening assay against a panel of four different human cancer cell lines, liver (HepG-2), colon (HCT-116), human cervical cancer (HeLa) and breast (MCF-7). Out of a library of 17 compounds, two compounds have been identified as potent and selective cytotoxic agents against HeLa and MCF-7 cell lines. SAR studies for such hybridized analogues were investigated and phenyl derivatives were proved to be more potent than isoxazole and triazole derivatives. Furthermore, the promising compounds were selected for in vitro inhibition of EGFR-TK and Topo II enzymes. Also, they were subjected to cell cycle arrest analysis and apoptosis assay on MCF-7 cells. Our recent finding highlights these thiophene-quinoline analogues as a promising class of compounds for further studies concerning new anticancer therapies.

Bioisosteric ferrocenyl aminoquinoline-benzimidazole hybrids: Antimicrobial evaluation and mechanistic insights

Phenyl- and bioisosteric ferrocenyl-derived aminoquinoline-benzimidazole hybrid compounds were synthesised and evaluated for their in vitro antiplasmodial activity against the chloroquine-sensitive NF54 and multi-drug resistant K1 strains of the human malaria parasite, Plasmodium falciparum. All compounds were active against the two strains, generally showing enhanced activity in the K1 strain, with resistance indices less than 1. Cytotoxicity studies using Chinese hamster ovarian cells revealed that the hybrids were relatively non-cytotoxic and demonstrated selective killing of the parasite. Based on favourable in vitro antiplasmodial and cytotoxicity data, the most active phenyl (4c) and ferrocenyl (5b) hybrids were tested in vivo against the rodent Plasmodium berghei mouse model. Both compounds caused a reduction in parasitemia relative to the control, with 5c displaying superior activity (92% reduction in parasitemia at 4 × 50 mg/kg oral doses). The most active phenyl and ferrocenyl derivatives showed inhibition of β-haematin formation in a NP-40 detergent-mediated assay, indicating a possible contributing mechanism of antiplasmodial action. The most active ferrocenyl hybrid did not display appreciable reactive oxygen species (ROS) generation in a ROS-induced DNA cleavage gel electrophoresis study. The compounds were also screened for their in vitro activity against Mycobacterium tuberculosis. The hybrids containing a more hydrophobic substituent had enhanced activity (<32.7 μM) compared to those with a less hydrophobic substituent (>62.5 μM).

Tethered N-Heterocyclic Carbene-Carboranyl Silver Complexes for Cancer Therapy

Silver complexes of tethered N-heterocyclic carbene-carboranyl ligands have been prepared and fully characterized. The first example of silver bonded directly to the cage of o-carborane has been identified in the solid state. The presence of a carboranyl N substituent on the N-heterocyclic carbene significantly enhances the in vitro cytotoxicity of the silver complex against HCT116 p53+/+ and HCT116 p53–/– colon cancer cells in comparison to a phenyl derivative. Conversely, the presence of a carboranyl on the backbone of a xanthine-derived N-heterocyclic carbene decreases the in vitro cytotoxicity of the silver complex in comparison to its phenyl derivative. Stability studies on the xanthine-derived ligands and complexes show that decomposition via deboronation occurs in hydrous dimethyl sulfoxide, which may attribute to the contrasting in vitro behaviors of the carborane-containing complexes.

Carphedon at the Crossroads: A Dangerous Drug or a Promising Psychopharmaceutical?

Carphedon is a phenyl derivative of the nootropic drug piracetam (Nootropil) and is effective in increasing physical endurance and cold resistance and is used for amnesia treatment. It was developed in Russia as a stimulant to keep astronauts awake on long missions, and occasionally used in Russia as a nootropic prescription for various types of neurological disease. It became well known a couple years ago when a leading nootropic supplier in California started selling it on the Internet as a supplement and a bunch of athletes got kicked out of the Olympics for illegal using it. Carphedon was found to activate the operant behavior more powerfully, to remove psychodepressant effects of diazepam, to inhibit post-rotational nystagmus, and to prevent the development of retrograde amnesia. Unlike piracetam, carphedon exhibits a specific anticonvulsant action. When given in high doses, produces psychodepressant effects. It is also claimed to increase physical stamina and provide improved tolerance to cold. As a result, it appears on the lists of banned substances issued by the World Anti-Doping Agency.

Inhibition of human cytochrome P450 2A6 by 7-hydroxycoumarin analogues: Analysis of the structure-activity relationship and isoform selectivity

Compared with coumarin, 7-hydroxycoumarin could serve as a better hit for developing CYP2A6 inhibitors. In this study, a series of 7-hydroxycoumarin and its structural analogues were collected to study their structure-activity relationship (SAR) and isoform selectivity for inhibiting CYP2A6. All tested coumarins except a C4 phenyl derivative (11) showed higher inhibitory activities for CYP2A6 over the other CYP isoforms, including CYP1A2, CYP2D6, CYP2E1, CYP3A4, CYP2C8, and CYP2C9. Of these coumarins, 6,7-dihydroxycoumarin (1) and 7,8-dihydroxycoumarin (9) were found to be potent inhibitors of CYP2A6 with IC50/Ki value of 0.39/0.25 and 4.61/3.02 μM, respectively, compared to methoxalen as positive control (IC50/Ki = 0.43/0.26 μM). In contrast, other coumarins showed low or decreased CYP2A6-inhibiting activities. SAR analysis showed that hydroxy groups might be important for CYP2A6 inhibition, and the rank order of sites for hydroxy substitution was C6 > C7 > C8. In addition, either hydrophobic or hydrophilic substituents introduced into C4, C6 and C8 led to a reduction in CYP2A6-inhibiting activity, and the degree of influence was dependent on the size and electrical charge of substituents. Furthermore, inhibition kinetic analysis and docking simulations demonstrated that the 8-O-glucosylated coumarin derivative (17) exhibited noncompetitive inhibition against CYP2A6, while competitive inhibition patterns were noted for the other tested coumarins. The mechanisms underlying the inhibitors binding to CYP2A6 were further investigated by molecular docking study. The findings presented herein are very helpful for developing highly selective and more potent CYP2A6 inhibitors.

The structural aspects of the transformation of 3-nitroisoxazoline-2-oxide to 1-aza-2,8-dioxabicyclo[3.3.0]octane derivatives: Experimental and MEDT theoretical study

Reaction of 3-nitroisoxazoline-2-oxide with monosubstituted ethenes, first time documented fifty years ago, have been reviewed. Structures of phenyl and cyano derivatives of 1-aza-2,8-dioxabicyclo[3.3.0]octane produced in [3 + 2] cycloaddition (32CA) between styrene and acrylonitrile with 3-nitroisoxazoline-2-oxide were determined through single crystal XRD analysis. The molecular mechanism of the title 32CA has been also analyzed within the Molecular Electron Density Theory (MEDT) based on the M06-2X(PCM)/6-311 + G(d,p) calculations.

Novel Tri-substituted Thiazoles Bearing Piperazine Ring: Synthesis and Evaluation of their Anticancer Activity

Background: Cancer cells are described as an unregulated growth and spread of abnormal cells. Recently, cancer has become the most important major reason for deaths in the world. Methods: For anticancer activity, we have used the MTT method and determine the early/late apoptosis by flow cytometry. Results: The title compounds were procured by reacting 2-chloro-N-[4-(pyridin-4-yl)thiazol-2- yl]acetamide with some substituted piperazine derivatives. The in vitro anticancer activity of synthesized compounds was tested against C6 rat glioma cells and A549 human lung carcinoma cells. As a result, the compounds 3d, 3e, 3f and 3g have shown anticancer activity against both cell line. Conclusion: Specifically, compound 3f was determined as the most active compound against C6 rat glioma cells. Also, as understood, the core structure which is substituted with piperazine bridge, the heterocyclic aromatic derivatives are more active than phenyl or benzyl derivatives.

Synthesis and electrochemical behaviour of rigid ferrocenyl-terminated pyridylphenylene dendrimers

The synthesis of ferrocenyl-terminated pyridylphenylene dendrimers based on trifunctional core via the Diels-Alder cycloaddition of ferrocenyl-containing cyclopentadienone and ethynyl terminated phenylene derivatives is presented. Dendrimers of two generations were synthesized and characterized using NMR, MALDI-TOF spectrometry and GPC. Cyclic voltammetry (CV) of the dendrimers shows single quasi-reversible wave. The strong adsorption occurs onto Pt and GC electrodes during CV in CH2Cl2, which is reflected by the high ipc/ipa ratio. Thus, a fabrication of modified Pt electrode with a ferrocenyl dendrimer is proved to be possible. The resulting electrode is stable towards CH2Cl2 washing and multiple CV scanning. The CV of the modified electrode shows an almost symmetrical response, which is typical for surface immobilized redox-active materials.

Luminescent NˆCˆN cyclometalated iridium(III) acetylide complexes with fluorene and carbazole motifs

NˆCˆN cyclometalated iridium(III) acetylide complexes in the 3 + 2+1 ligand mode were obtained and characterized. Cyclometalating ligands were bis(pyridyl)phenyl, bis(benzothiazolyl)phenyl and 2-phenylpyridine derivatives, while acetylene ligands represented 2-ethynylfluorene and 3-ethynylcarbazole derivatives. The HOMOs of the ethynyl iridium complexes are located on the ethynyl ligand and the iridium atom, whereas the LUMO is located exclusively on the NˆCˆN-cyclometalating ligand. All compounds showed phosphorescent properties, where the change of ligands significantly affects the wavelength of emission. Acetylide complexes emit light from the blue (∼ 400 nm) to orange (∼ 560 nm) range. Emission occurs from the mixed state 3 MLCT/ 3 LC, with a predominance of junction depending on the structure of the ligands. • Iridium acetylide complexes with fluorene and carbazole motifs were examined. • Detailed characterization of optical, thermal and electrochemical properties of new complexes has been carried out. • In the Ir(III) complexes the emission takes place from the mixed state 3 MLCT/ 3 LC.

Hollow and Solid Spheres Assembled from Functionalized Macrocycles Containing Adamantane.

An adamantane-based macrocycle possessing eight hydroxyl groups (1) was synthesized, in which the macrocyclic framework comprises two disubstituted adamantane molecules bearing phenyl derivatives connected to two biphenylene spacers by oxygen atoms. Furthermore, functionalized macrocycles containing methyl (2) and methoxycarbonylmethyl (3) groups were prepared. From the X-ray crystallographic analysis, the backbone of the macrocycles in all crystals had a nearly hexagonal shape with a cavity and these macrocycles could be arranged into different tubular structures dependent on the substituents. In acetone, macrocycle (1) formed stable hollow spherical aggregates with multilayer membranes. In contrast, macrocycle (3) exhibited no production of self-assembled materials in chloroform. The addition of hexane into the solution caused the generation of solid spheres and their fused network aggregates, which were finally transformed into crystals owing to the solvent effects.