Central Phenyl Research Articles

Intramolecular Torsion Based Molecular Switch Functionality Enhanced in π-Conjugated Oligomolecules by a π-Conjugated Pendant Group

Theoretical investigations of the variation of junction conductance with the intramolecular twist in π-conjugated oligomolecules induced by a pendant group and its effects on the enhancement in its molecular switch functionality are presented. The pendant group is found to introduce “through space” electronic coupling between the central phenyl group and its adjacent ethynylenes in the highest occupied molecular orbital, which opens an additional tunnel channel. Consequently, the π-conjugation in the backbone of the molecule is reinforced and the junction conductance along the molecular backbone gets elevated relative to the parent molecule. A 90° intramolecular twist angle of the molecule is regarded as the “OFF” state for its lowest conductance at this exactly perpendicular conformation, while the other twist angles including 0° are considered as “ON states” of the molecule. The pendant group raises the ratio of the junction conductance between the “ON” and “OFF” states by up to 2 orders of magnitude, t...

1,4-Bis[(1H-pyrazol-1-yl)methyl]benzene

In the title compound, C14H14N4, the center of the phenyl­ene group is a crystallographic center of inversion. The compound is composed of three aromatic rings displaying a Z-like conformation. The dihedral angle between the pyrazole rings and the central phenyl ring is 83.84 (9)°.

Excited-State Processes in First-Generation Phenyl-Cored Thiophene Dendrimers

First generation dendrimers with three oligothiophene arms (meta-arranged, 3G1-nS) and four arms (ortho- and para-arranged, 4G1-nS) connected to a central phenyl core were investigated spectroscopically in solution. In all dendrimers, on an ultrafast time scale (<10 ps), two "cooling" processes convert the initially generated, "hot" exciton into the geometrically relaxed, "cold" exciton. A decrease in the triplet yield, particularly evident for the 4-arm dendrimers; intersystem crossing rate; and nonradiative triplet decay time with increasing number of bridging thiophene units n all meet with expectations from prior studies on linear oligothiophenes. A relatively fast internal conversion process (>0.6 ns(-1)) is observed in both dendrimer series, possibly due to increased twisting about the phenyl core that reduces the triplet yields considerably with respect to oligothiophenes. An anomalous shifting of the triplet-triplet absorption spectra characterizes the 4G1-nS dendrimers as unique from the 3G1-nS series in terms of the hindrance of torsional motion and confinement of excited states enforced by the arrangement of dendrons.

In Silico Quantitative Structure-Activity Relationship Studies on P-gp Modulators of Tetrahydroisoquinoline-Ethyl-Phenylamine Series

BackgroundMultidrug resistance (MDR) is a major obstacle in cancer chemotherapy. The drug efflux by a transport protein is the main reason for MDR. In humans, MDR mainly occurs when the ATP-binding cassette (ABC) family of proteins is overexpressed simultaneously. P-glycoprotein (P-gp) is most commonly associated with human MDR; it utilizes energy from adenosine triphosphate (ATP) to transport a number of substrates out of cells against concentration gradients. By the active transport of substrates against concentration gradients, intracellular concentrations of substrates are decreased. This leads to the cause of failure in cancer chemotherapy.ResultsHerein, we report Topomer CoMFA (Comparative Molecular Field Analysis) and HQSAR (Hologram Quantitative Structure Activity Relationship) models for third generation MDR modulators. The Topomer CoMFA model showed good correlation between the actual and predicted values for training set molecules. The developed model showed cross validated correlation coefficient (q2) = 0.536 and non-cross validated correlation coefficient (r2) = 0.975 with eight components. The best HQSAR model (q2 = 0.777, r2 = 0.956) with 5-8 atom counts was used to predict the activity of test set compounds. Both models were validated using test set compounds, and gave a good predictive values of 0.604 and 0.730.ConclusionsThe contour map near R1 indicates that substitution of a bulkier and polar group to the ortho position of the benzene ring enhances the inhibitory effect. This explains why compounds with a nitro group have good inhibitory potency. Molecular fragment analyses shed light on some essential structural and topological features of third generation MDR modulators. Fragments analysis showed that the presence of tertiary nitrogen, a central phenyl ring and an aromatic dimethoxy group contributed to the inhibitory effect. Based on contour map information and fragment information, five new molecules with variable R1 substituents were designed. The activity of these designed molecules was predicted by the Topomer CoMFA and HQSAR models. The novel compounds showed higher potency than existing compounds.

4-(1-Ethyl-1H-1,3-benzimidazol-2-yl)-N,N-diphenylaniline monohydrate

In the title compound, C27H23N3O·H2O, the benzimidazole ring system has an r.m.s. deviation of 0.0071 Å and makes dihedral angles of 34.51 (2), 55.22 (3) and 41.05 (5)° with the central and N-bonded phenyl rings, respectively. In the crystal, the water mol­ecular is connected to the organic mol­ecule by inter­molecular O—H⋯N hydrogen bonds. Weak inter­molecular C—H⋯O hydrogen bonds also occur.

Synthesis, Characterization and Properties of 1,4-Bis(Naphthalen-1-Ylethynyl)Benzene and Its Derivatives: Monomers of Oligomers or Polymers Based on Linear 1,4-Phenylethynyl or 1,5-Naphthylethynyl Subunits

A series of novel monomers of oligomers or polymers based on linear 1,4-phenylethynyl or 1,5-naphthylethynyl subunits, 1,4-bis(naphthalen-1-ylethynyl)benzene (8a) and its derivatives (8b–8i), has been synthesized and characterized. The UV absorption and fluorescence emission properties of these compounds were analyzed and discussed through the energy gap ( E ) between HOMO and LUMO orbitals, the orbital diagrams and the charge densities of related carbon atoms. It is evident from these results that the introduction of the electron-donating substituent (–OR) to the central phenylene ring of 8a and the introduction of electron-withdrawing substituent (–NO2) to the end of the conjugated system can efficiently improve its solubility, give rise to red-shift of maximum absorption and emission wavelength. But the introduction of electron-withdrawing substituent (–NO2) will lead dramatically decrease in fluorescence efficiency. The novel synthesized compounds 8b–8e have potential prospects as the monomers of oligomers or polymers based on linear 1,4-phenylethynyl or 1,5-naphthylethynyl subunits for their excellent solubility and optical properties.

1,4-Bis(2,2′:6′,2′′-terpyridin-4′-yl)benzene

The asymmetric unit of the title compound, C36H24N6, comprises a whole mol­ecule. Supra­molecular inter­actions between neighbouring mol­ecules are essentially π–π stacking inter­actions with small inter­planar distances [3.5140 (15) and 3.6041 (15) Å]. The central phenyl­ene ring is tilted with respect to the two pyridine substituents, subtending angles of 36.17 (11) and 34.95 (11)°. Three of the peripheral pyridine substituents are almost coplanar with the central pyridines [dihedral angles = 5.10 (12)-8.21 (12)°], but one subtends an angle of 24.86 (12)°.

Phenolic Bis-styrylbenzenes as β-Amyloid Binding Ligands and Free Radical Scavengers

Starting from bisphenolic bis-styrylbenzene DF-9 (4), β-amyloid (Aβ) binding affinity and specificity for phenolic bis-styrylbenzenes, monostyrylbenzenes, and alkyne controls were determined by fluorescence titration with β-amyloid peptide Aβ(1-40) and a fluorescence assay using APP/PS1 transgenic mouse brain sections. Bis-styrylbenzene SAR is derived largely from work on symmetrical compounds. This study is the first to describe Aβ binding data for bis-styrylbenzenes unsymmetrical in the outer rings. With one exception, binding affinity and specificity were decreased by adding and/or changing the substitution pattern of phenol functional groups, changing the orientation about the central phenyl ring, replacing the alkene with alkyne bonds, or eliminating the central phenyl ring. The only compound with an Aβ binding affinity and specificity comparable to 4 was its 3-hydroxy regioisomer 8. Like 4, 8 crossed the blood-brain barrier and bound to Aβ plaques in vivo. By use of a DPPH assay, phenol functional groups with para orientations seem to be a necessary, but insufficient, criterion for good free radical scavenging properties in these compounds.

Indole- and benzothiophene-based histamine H 3 antagonists

Previous research on histamine H 3 antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH 3 affinities. Select analogs were profiled in a rat pharmacokinetic model.

ChemInform Abstract: Synthesis and Biological Evaluation of a Series of 1,1-Dichloro-2,2,3- triarylcyclopropanes as Pure Antiestrogens.

A series of 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs) was synthesized and evaluated as pure antiestrogens. Addition of 4-methoxy- or 4-(benzyloxy)phenyl Grignard reagents to p-methoxy, p-benzyloxy, or unsubstituted deoxybenzoins, followed by dehydration of the resulting carbinols produced a mixture of E and Z olefins, which were reacted with dichlorocarbene to give O-protected DTACs. The E and Z isomers were separated by fractional crystallization and the central or geminal phenyl ring was deprotected to provide phenolic DTACs. Alkylation with (N,N-dimethylamino)ethyl chloride yielded basic cyclopropanes. Two chlorodiarylindenes were isolated as thermolysis products of the DTACs, and one was converted to a phenol by hydrogenolysis. All DTACs and indenes were competitive inhibitors of [3H]estradiol binding in the immature rat uterine cytosol receptor assay, with relative binding affinities of 0.1-3.6% of estradiol. None of the new compounds were estrogenic in the 3-day immature mouse uterotrophic assay at doses up to 750 micrograms. In the 3-day immature mouse antiuterotrophic assay, five DTACs with either a methoxy (5a), benzyloxy (4d, 5c), or (dimethylamino)ethoxy (7a, 7b) central ring side chain produced significant decreases in uterine weight at doses up to 750 micrograms. One compound, (Z)-1,1-dichloro-2-[4-[2-(dimethylamino)ethoxy]-phenyl]-2-(4- methoxyphenyl)-3-phenylcyclopropane (7b), elicited a dose-dependent decrease in vivo comparable to MER 25. These same five compounds, as well as the lead compound Analog II, were active in vitro against the estrogen-dependent MCF-7 human breast tumor cell line in a dose-dependent fashion.

ChemInform Abstract: Synthesis and Characterization of New Conjugation-Extended Viologens Involving a Central Aromatic Linking Group.

New viologens, in which two pyridinium moieties are linked by a central five-membered heteroaromatic or phenylene framework, giving stable radical cations on single electron reduction and showing an intense fluorescence emission are efficiently synthesized and characterized.

Effect of lateral substitution on supramolecular liquid crystal associates induced by hydrogen-bonding interactions between 4-(4′-pyridylazo-3-methylphenyl)-4′′-alkoxy benzoates and 4-substituted benzoic acids

Five laterally methyl-substituted pyridine-based derivatives of the title compounds (I 8–I 16), with molecular formula 4-CnH2n+1O-C6H4COOC6H3(3-CH3)-N=N-C5H4N were prepared and their molecular formulae elucidated via elemental analyses, infrared, nuclear magnetic resonance and mass spectra. The number of carbon atoms in the alkoxy chain (n) varies between 8, 10, 12, 14, and 16 carbons. The newly prepared pyridine-based derivatives were investigated for their mesophase behaviour by differential scanning calorimetry and polarised optical microscopy; most of them were found to possess monotropic smectic C (SmC) mesophase. Two groups (A and B) of the 1:1 hydrogen-bonded associates, formed between each of the derivatives I 8– I 16 and two types of 4-substituted benzoic acids (II), were prepared and similarly characterised to investigate the effect of lateral methyl substitution on the central phenylene ring, as well as terminal polar substituents and alkoxy-chain length on the stability of the mesophases induced by intermolecular hydrogen bonding. In Group A complexes, mesomorphic 4-alkoxy benzoic acids, that carry the terminal n-alkoxy group of varying chain length, were used. The other series of complexes (Group B) is composed from the same pyridine-based derivatives and each of the non-mesomorphic 4-substituted benzoic acids that carries small compact polar groups, varying between CH3O, CH3, H, Cl, Br, and CN. All complexes prepared were investigated for their mesophase behaviour by differential scanning calorimetry and polarised optical microscopy and found to be purely smectogenic, possessing SmC as the only mesophase observed. The formation of the hydrogen-bonded complexes was confirmed by constructing their binary phase diagrams, which cover the whole range of concentration of the two complements.

Leukotriene B4 inhibitors: US2009054466; US2009227603 and US2009253684

Three US applications describing a narrow, closely related series of antagonists of the action of leukotriene B4 on the BLT1 and BLT2 receptors are described. The generic structure claimed is a lipophilic linked diphenyl core containing two acid groups appended to the central phenyl ring. The terminal phenyl moiety contains disubstitution at the 3′- and 5′-positions. These three applications differ in the nature of the substituent on the terminal phenyl group as well as the linking moiety between the two phenyl rings. These compounds are claimed to have utility in inflammatory diseases such as severe asthma and chronic obstructive pulmonary disease.

1,3-Bis(phenylsufanylmethyl)benzene

The complete mol­ecule of the title compound, C20H18S2, is generated by crystallographic mirror symmetry, with two C atoms lying on the mirror plane. All of the independent atoms are contained within two planes defined by the thio­phenyl rings (C6S) and the central phenyl ring with the methyl­ene bridge; the r.m.s deviations of these planes are 0.012 and 0.025 Å, respectively. The two planes are almost perpendicular to one another at a dihedral angle of 80.24 (10)°. Inter­molecular C—H—π inter­actions are present in the crystal structure.

BRAF Inhibitors Based on an Imidazo[4,5]pyridin-2-one Scaffold and a Meta Substituted Middle Ring

We recently reported on the development of a novel series of BRAF inhibitors based on a tripartite A-B-C system characterized by a para-substituted central aromatic core connected to an imidazo[4,5]pyridin-2-one scaffold and a substituted urea linker. Here, we present a new series of BRAF inhibitors in which the central phenyl ring connects to the hinge binder and substrate pocket of BRAF with a meta-substitution pattern. The optimization of this new scaffold led to the development of low-nanomolar inhibitors that permits the use of a wider range of linkers and terminal C rings while enhancing the selectivity for the BRAF enzyme in comparison to the para series.

Solid state stabilisation of the orally delivered drugs atenolol, glibenclamide, memantine and paracetamol through their complexation with cucurbit[7]uril

The inclusion of the cardiovascular beta-blocker drug atenolol, the antidiabetic drug glibenclamide, the Alzheimer's NMDA glutamate receptor drug memantine and the analgesic/antipyretic drug paracetamol by cucurbit[7]uril (CB[7]) has been studied by (1)H nuclear magnetic resonance spectroscopy, electrospray ionisation mass spectrometry, molecular modelling, fluorescence displacement assays and differential scanning calorimetry. All four drugs form 1 : 1 host-guest complexes with CB[7], but the exchange kinetics and location of the binding is different for each drug. Atenolol is bound over the central phenyl ring with a binding constant of 4.2 x 10(4) M(-1), whereas glibenclamide is bound over the terminal cyclohexyl group with a binding constant of 1.7 x 10(5) M(-1), and memantine is totally bound within the CB[7] cavity. Paracetamol is bound in two locations, over the central phenyl ring and over the methyl group, with the CB[7] molecule shuttling quickly between the two sites. Inclusion by CB[7] was shown by differential scanning calorimetry to physically stabilise all four drugs, which has applications preventing drug degradation and improving drug processing and formulation.

Synthesis and solid state characterization of molecular rotors with steroidal stators: ethisterone and norethisterone

In this article we describe the synthesis and dynamic behavior of two new molecular rotors with 1,4-diethynylphenylene rotators axially linked to two conformationally rigid steroidal norethisterone acetate or ethisterone frames. The resulting 1,4-bis(19-nor-17alpha-ethynyltestosterone-17beta-acetate)benzene (1) and 1,4-bis(17alpha-ethynyltestosterone)benzene (2) were fully characterized in solution and in the solid state, and the rotational dynamics of the central phenylene were explored with the help of (13)C NMR with cross polarization and magic angle spinning (CPMAS), and with quadrupolar echo variable temperature (VT) (2)H NMR in the case of 1. Splitting of signals from the aromatic ring on the (13)C CPMAS NMR and a broad quadrupolar spin echo (2)H spectrum of polycrystalline samples indicated that the rotation of the central aromatic ring in these compounds was limited at ambient temperature in the solid state. Variable temperature (2)H NMR experiments at 350 K in the case of 1-d(4) suggested a 2-fold rotational exchange with upper frequency limit of ca. 10 kHz. Single crystal X-ray analysis of this compound revealed that a crowded environment around the prospective phenylene rotator is responsible of the restricted rotation in the solid state.

New Bimetallic Reactivity in Pt2II,II/Pt2IV,IV Transformation Mediated by a Benzene Ring

A new Pt2II,II complex with the formula Pt2(TPAB)Me4 (1), where TPAB = 1,2,4,5-tetrakis(5-(p-C7H15Ph)-7-azaindol-1-yl)benzene, has been synthesized. This molecule has excellent solubility in common solvents, which enabled our investigation of its reactions with a variety of oxidants to form Pt2IV,IV species and the reverse reactions of the Pt2IV,IV species back to 1 via reduction. Despite the lack of direct Pt···Pt interactions, the two Pt centers in 1 display distinct bimetallic cooperativity mediated by the central phenyl ring of the TPAB ligand. The most unusual finding is that the reactivity of 1 with MeOTf is highly dependent on the amount of molecular oxygen present in the reaction medium. In the absence of O2, the reaction of 1 with MeOTf produced [Pt2IV,IV(TPAB)Me6][OTf]2 (6), while in the presence of O2, complex 7, Pt2IV,IV(TPAB)Me4(OTf)2, was obtained. Compound 1 was found to react readily with O2 at one atmosphere and ambient temperature to produce an insoluble and not yet fully characterized s...

Design and Synthesis of Imidazopyrimidine Derivatives as Potent iNOS Dimerization Inhibitors.

A series of imidazopyrimidine derivatives with the general formula I was synthesized and identified as potent inhibitors of iNOS dimer formation, a prerequisite for proper functioning of the enzyme. Stille and Negishi coupling reactions were used as key steps to form the carbon-carbon bond connecting the imidazopyrimidine core to the central cycloalkenyl, cycloalkyl and phenyl ring templates.

1-(2-Bromobenzyl)-3-isopropylbenzimidazolin-2-one

In the structure of the title compound, C17H17BrN2O, the central phenyl and imidazol-2-one rings are coplanar (dihedral angle between planes of 0.73 (11)°). The angles subtended by the substituents on the N atoms of the imidazol-2-one ring range from 109.71 (14)° to 128.53 (15) due to steric hindrance of these substituents with the phenyl H atoms. The carbonyl O and Br both make two weak C—H⋯O and C—H⋯Br inter­actions with two adjacent mol­ecules, thus forming an three-dimensional array.