Substituted Phenyl Ring Research Articles

DFT and experimental (FT-IR and FT-Raman) investigation of vibrational spectroscopy and molecular docking studies of 2-(4-oxo-3-phenethyl-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl) acetamide

A comprehensive structural and vibrational study of 2-(4-oxo-3-phenethyl-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl) acetamide is reported. FT-IR and FT-Raman wavenumbers were compared with the theoretical values obtained from DFT calculations. Theoretical values agree well with the experimental values. Molecular electrostatic potential, frontier molecular orbital analysis and nonlinear optical properties were investigated using theoretical calculations. Natural bond orbital analysis shows that charge in electron density in σ* and π* antibonding orbitals and E(2) energies confirms the occurrence of intermolecular charge transfer within the molecule. Nonlinear optical property has also observed by predicting the first and second order hyperpolarizability parameters. As can be seen from the molecular electrostatic potential map of the title molecule, negative region is mainly localized over the carbonyl groups and the mono substituted phenyl ring and the maximum positive region is localized on the NH and hydrogen atoms. Molecular docking results show that the docked ligand title compound forms a stable complex with BRCA2 complex and gives a binding affinity value of −7.6 kcal/mol and results suggest that the compound might exhibit inhibitory activity against BRCA2 complex.

A facile approach towards increasing the nitrogen-content in nitrogen-doped carbon nanotubes via halogenated catalysts

Nitrogen-doped carbon nanotubes (N-CNTs) have been synthesized at 850°C via a CVD deposition technique by use of three ferrocenyl derivative catalysts, i.e. para-CN, -CF3 and -Cl substituted-phenyl rings. The synthesized catalysts have been characterized by NMR, IR, HR-MS and XRD. The XRD analysis of the para-CF3 catalyst indicates that steric factors influence the X-ray structure of 1,1′-ferrocenylphenyldiacrylonitriles. Acetonitrile or pyridine was used as carbon and nitrogen sources to yield mixtures of N-CNTs and carbon spheres (CS). The N-CNTs obtained from the para-CF3 catalysts, in pyridine, have the highest nitrogen-doping level, show a helical morphology and are less thermally stable compared with those synthesized by use of the para-CN and -Cl as catalyst. This suggests that fluorine heteroatoms enhance nitrogen-doping in N-CNTs and formation of helical-N-CNTs (H-N-CNTs). The para-CF3 and para-Cl catalysts in acetonitrile yielded iron-filled N-CNTs, indicating that halogens promote encapsulation of iron into the cavity of N-CNT. The use of acetonitrile, as carbon and nitrogen source, with the para-CN and -Cl as catalysts also yielded a mixture of N-CNTs and carbon nanofibres (CNFs), with less abundance of CNFs in the products obtained using para-Cl catalysts. However, para-CF3 catalyst in acetonitrile gave N-CNTs as the only shaped carbon nanomaterials.

Anti-bacterial and in vitro Anti-diabetic Potential of Novel Isoxazole Derivatives

Aim: To synthesize novel Isoxazole derivatives, characterize them and subject for screening anti-bacterial action and in vitro anti-diabetic activity. Methodology: Chalcones were prepared by the reaction of aromatic aldehydes with aromatic ketones in aqueous alcoholic alkaline medium. Then these were made to react with hydroxylamine hydrochloride and sodium acetate to prepare title compounds. The prepared isoxazole compounds were subjected to in vitro anti-diabetic screening by yeast and enzymatic method. All compounds were screened for antibacterial action by disc diffusion method. Results: The structure of the synthesized compounds were confirmed by IR, NMR spectral datas and screened for anti-bacterial, and anti-diabetic activities. Most effective antibacterial one possessed chlorine in the Phenyl ring attached at 5-C of isoxazole and have NH2 substitution in phenyl ring attached at 3-C of isoxazole. Compounds with significant in vitro anti-diabetic action by studying the glucose uptake by yeast cell method are with Br/NO2 substituted forR2/R3 in phenyl ring when R’2 is OH/NH2. Conclusion: Presence of halogenated aromatic ring at 5-C and amine substituted phenyl ring at 3-Cof Isoxazole exhibited moderate anti-bacterial activity. In the anti-diabetic study halogenated or nitrated phenyl ring at 5-C and hydroxyl/amine substituted phenyl ring at 3-C of isoxazole exhibited anti-diabetic action.

Synthesis of novel azoester homologous series of liquid crystalline behavior and the study of mesomorphism dependence on lateral substitution of middle phenyl ring

ABSTRACTThe titled azoester liquid crystalline homologous series consists of eleven homologues. The pentyl to tetradecyl derivatives of the series are nematogenic without exhibition of smectogenic character. Rest of the members of the series are nonliquid crystalline in nature. Textures of the nematic mesophase are schlieren or threaded type. Transition curves in the phase diagram showed normal phase behavior. Transition temperatures and liquid crystal behavior observed under an optical polarizing microscope equipped with a heating stage. An odd even effect is observed for nematic-isotropic transition curve. Analytical and spectral data confirms the structures of the molecules. Present homologous series is predominant nematogenic and partly nonmesogenic. Average thermal stability for nematic is 125.33°C and nematogenic mesophase length varies between 12°C to 48°C at tetradecyl (C14) and octyl (C8) derivatives, respectively.

Statistical Analysis of the Impact of Molecular Descriptors on Cytotoxicity of Thiourea Derivatives Incorporating 2-Aminothiazole Scaffold.

Chemical reactivity descriptors and lipophilicyty (log P) were evaluated via semi-empirical method for the quantum calculation of molecular electronic structure (PM3) in order to clarify the structure-cytotoxic activity relationships of disubstutited thioureas. Analysed compounds were obtained by the linkage of 2-aminothiazole ring, thiourea and substituted phenyl ring. The detailed examination was carried out to establish correlation between descriptors and cytotoxic activity against the MT-4 cells for 11 compounds. For the most active compounds (6 compounds) cytotoxic activity against three cancer cell lines (CCRF-CEM, WIL-2NS, CCRF-SB) and normal human cell (HaCaT) was determined. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction and lactate dehydrogenase (LDH) release were assessed. Regression analysis revealed that electrophilicity index and chemical potential significantly contributed to expain the thioureas cytotoxic potential.

A new synthesis strategy for acridine derivatives to constructing novel host for phosphorescent organic light-emitting diodes

A new intermediate, 3-bromo-9,9-diphenyl-9,10-dihydroacridine, based on 9,10-dihydroacridine was synthesized and thereby a new host material, 2,6-bis(9,9,10-triphenyl-9,10-dihydroacridin-3-yl)pyridine, via the intermediate was designed and prepared. This intermediate directed a meta-derivation and could make the resulted host retain triplet energy of 2.68 eV. Besides, the rigid backbone along with the substituted phenyl rings at C9 position could benefit the thermal and morphological stabilities of host. According to these features arise from the key intermediate, blue and red phosphorescent organic light-emitting diodes were fabricated and external quantum efficiencies above 10% were achieved with relative flat roll-off.

Solid-state Porphyrin Interactions with Oppositely Charged Peripheral Groups.

The crystallization and the crystal and molecular structure of a very slightly soluble electrostatically interacting pair of porphyrins is described. The tetra-anion 5,10,15,20-tetrakis-(4-sulfonatophenyl)-21,23H-porphyrin [H2TPPSO3]4- and the tetra-cation 5,10,15,20-tetra(N-methylpyridyl)21H,23H-porphyrin [H2TMePyP]4+ are found to form an alternating one-dimensional stack that is stabilised by electrostatic interactions between the porphyrin rings but also by π-π interactions between all substituted phenyl rings in the ensemble. The resulting interactions between the porphyrins is exceptionally tight.

Synthesis of New Arylmethylene Derivatives of Resorcinarene via the Catalyzed Mannich Reaction

The C-arylation of Mannich base is used to obtain a series of new arylmethylene resorcinarene derivatives. Initially, aminomethyl derivative as the intermediate is formed in the Mannich reaction of resorcinarene with iminodiacetic acid. Next, activated aromatic rings act as a nucleophile in the reaction with this Mannich base and the arylmethylene derivatives of resorcinarene are prepared. The mixture of isomeric products is obtained for monosubstituted phenyl rings. Reaction with a suitably substituted phenyl ring gives one main product in good yields.

Triazole linked mono carbonyl curcumin-isatin bifunctional hybrids as novel anti tubulin agents: Design, synthesis, biological evaluation and molecular modeling studies

Keeping in view the limitations associated with currently available anticancer drugs, molecular hybrids of mono carbonyl curcumin and isatin tethered by triazole ring have been synthesized and evaluated for in vitro cytotoxicity against THP-1, COLO-205, HCT-116, A549, HeLa, CAKI-I, PC-3, MiaPaca-2 human cancer cell lines. The results revealed that the compounds SA-1 to SA-9, SB-2, SB-3, SB-4, SB-7 and SC-2 showed a good range of IC50 values against THP-1, COLO-205, HCT-116 and PC-3 cell lines, while the other four cell lines among these were found to be almost resistant. Structure activity relationship revealed that the nature of Ring X and substitution at position R influences the activity. Methoxy substituted phenyl ring as Ring X and H as R were found to be the ideal structural features. The most potent compounds (SA-2, SA-3, SA-4, SA-7) were further tested for tubulin inhibition. Compound SA-2 was found to significantly inhibit the tubulin polymerization (IC50=1.2μM against HCT-116). Compound SA-2, moreover, lead to the disruption of microtubules as confirmed by immunofluorescence technique. The significant cytotoxicity and tubulin inhibition by SA-2 was streamlined by molecular modeling studies where it was docked at the curcumin binding site of tubulin.

Design and Synthesis of Imidazopyrazolopyridines as Novel Selective COX-2 Inhibitors.

The usefulness of non-steroidal anti-inflammatory drugs (NSAIDs) is hampered by their gastrointestinal side effects. Non-selective cyclooxygenases inhibitors interfere with both COX-1 and COX-2 isozymes. Since COX-1 mediates cytoprotection of gastric mucosa, its inhibition leads to the undesirable side effects. On the other hand, COX-2 is undetectable in normal tissues and selectively induced by inflammatory stimuli. Therefore, it is strongly believed that the therapeutic benefits derive from inhibition of COX-2 only. The presence of a strong connection between reported COX-2 inhibitors and cardiac toxicity encourages medicinal chemists to explore new scaffolds. In the present study, we introduced imidazopyrazolopyridines as new potent and selective COX-2 inhibitors that lack the standard pharmacophoric binding features to hERG. Starting from our lead compound 5a, structure-based drug-design was conducted and more potent analogues were obtained with high COX-2 selectivity and almost full edema protection, in carrageenan-induced edema assay, in case of compound 5e. Increased bulkiness around imidazopyrazolopyridines by adding a substituted phenyl ring(s) afforded less active compounds.

Regioisomeric and enantiomeric analyses of 24 designer cathinones and phenethylamines using ultra high performance liquid chromatography and capillary electrophoresis with added cyclodextrins

Designerphenethylamines (PEAs) and cathinones have been encountered worldwide. Complete characterization of these substances can be challenging due to their chirality and variably substituted phenyl rings. In this study, 24 PEAs and cathinones were analyzed by ultra high performance liquid chromatography with photo diode array detection (UHPLC-PDA) on a variety of stationary phases, and by capillary electrophoresis on a dynamically coated capillary with PDA detection (CE-PDA). In the UHPLC-PDA study, a BEH Phenyl column resolved 18 of the 24 regioisomers in 8min, with good discrimination of the PEAs. In contrast, capillary zone electrophoresis (CZE) on a dynamically coated capillary partially or baseline resolved only 10 of the 24 regioisomers, but with improved discrimination of mono-substituted cathinones. A second series of CE-PDA experiments using 80mM (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) in the run buffer resolved all 24 regioisomers and all but two sets of enantiomers within 18min. Five illicit samples were successfully analyzed using the described methods.

Lowering the pKa of a bisimidazoline lead with halogen atoms results in improved activity and selectivity against Trypanosoma brucei in vitro

Diphenyl-based bis(2-iminoimidazolidines) are promising antiprotozoal agents that are curative in mouse models of stage 1 trypanosomiasis but devoid of activity in the late-stage disease, possibly due to poor brain penetration caused by their dicationic nature. We present here a strategy consisting in reducing the pKa of the basic 2-iminoimidazolidine groups though the introduction of chlorophenyl, fluorophenyl and pyridyl ring in the structure of the trypanocidal lead 4-(imidazolidin-2-ylideneamino)-N-(4-(imidazolidin-2-ylideneamino)phenyl)benzamide (1). The new compounds showed reduced pKa values (in the range 1–3 pKa units) for the imidazolidine group linked to the substituted phenyl ring. In vitro activities (EC50) against wild type and resistant strains of T. b. brucei (s427 and B48, respectively) were in the submicromolar range with four compounds being more active and selective than 1 (SI > 340). In particular, the two most potent compounds (3b and 5a) acted approximately 6-times faster than 1 to kill trypanosomes in vitro. No cross-resistance with the diamidine and melaminophenyl class of trypanocides was observed indicating that these compounds represent interesting leads for further in vivo studies.

Microwave-assisted synthesis, characterisation and mesomorphic investigations of novel disubstituted aroylhydrazones

The present study is focused on the development of green microwave process for the synthesis of mesogenic substituted aroylhydrazones and their structure–mesophase relationship study. Two new liquid crystalline series of disubstituted aroylhydrazones with (ABB(OH)H-n) and without lateral hydroxyl group (ABBH-n) (n = 6–16) have been synthesised by microwave-assisted methods. The compounds were structurally characterised by using suitable spectroscopic techniques. The mesomorphic properties of the series of aroylhydrazones were examined using differential scanning calorimetric analysis and polarising optical microscopy. The relationship between structure and mesogenic properties was analysed by comparison of the present series and earlier reports on homostructural series of aroylhydrazones. Thus, the effects of substitution of phenyl rings with ester and ether linking group at both terminals and introduction of hydroxyl group at lateral position on stability of mesophase and their width were investigated. In general, all substituted aroylhydrazone derivatives exhibit SmC mesophase, and substitution of terminal and lateral group has considerably increased the stability and broadened the width of mesophase of the compounds.

Design and biological evaluation of novel 4-(2-fluorophenoxy)quinoline derivatives bearing an imidazolone moiety as c-Met kinase inhibitors

A series of 4-(2-fluorophenoxy)quinoline derivatives containing an imidazolone moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, H460, HT-29 and MKN-45). Most compounds showed moderate to excellent activities in enzyme and cellular assays. The most promising analog, 58 (c-Met IC50=1.42nM), displayed 2.1-, 8.6-fold increase against H460, and MKN-45 cell lines, respectively, compared with foretinib. An analysis of structure–activity relationships revealed that an ortho substituted phenyl ring as well as an N-unsubstituted imidazolone linker is favorable for antitumor activity.

Energy-Level Engineering at ZnO/Oligophenylene Interfaces with Phosphonate-Based Self-Assembled Monolayers.

We used aromatic phosphonates with substituted phenyl rings with different molecular dipole moments to form self-assembled monolayers (SAMs) on the Zn-terminated ZnO(0001) surface in order to engineer the energy-level alignment at hybrid inorganic/organic semiconductor interfaces, with an oligophenylene as organic component. The work function of ZnO was tuned over a wide range of more than 1.7 eV by different SAMs. The difference in the morphology and polarity of the SAM-modified ZnO surfaces led to different oligophenylene orientation, which resulted in an orientation-dependent ionization energy that varied by 0.7 eV. The interplay of SAM-induced work function modification and oligophenylene orientation changes allowed tuning of the offsets between the molecular frontier energy levels and the semiconductor band edges over a wide range. Our results demonstrate the versatile use of appropriate SAMs to tune the energy levels of ZnO-based hybrid semiconductor heterojunctions, which is important to optimize its function, e.g., targeting either interfacial energy- or charge-transfer.

Enhanced ligand sampling for relative protein-ligand binding free energy calculations.

Free energy calculations are used to study how strongly potential drug molecules interact with their target receptors. The accuracy of these calculations depends on the accuracy of the molecular dynamics (MD) force field as well as proper sampling of the major conformations of each molecule. However, proper sampling of ligand conformations can be difficult when there are large barriers separating the major ligand conformations. An example of this is for ligands with an asymmetrically substituted phenyl ring, where the presence of protein loops hinders the proper sampling of the different ring conformations. These ring conformations become more difficult to sample when the size of the functional groups attached to the ring increases. The Adaptive Integration Method (AIM) has been developed, which adaptively changes the alchemical coupling parameter λ during the MD simulation so that conformations sampled at one λ can aid sampling at the other λ values. The Accelerated Adaptive Integration Method (AcclAIM) builds on AIM by lowering potential barriers for specific degrees of freedom at intermediate λ values. However, these methods may not work when there are very large barriers separating the major ligand conformations. In this work, we describe a modification to AIM that improves sampling of the different ring conformations, even when there is a very large barrier between them. This method combines AIM with conformational Monte Carlo sampling, giving improved convergence of ring populations and the resulting free energy. This method, called AIM/MC, is applied to study the relative binding free energy for a pair of ligands that bind to thrombin and a different pair of ligands that bind to aspartyl protease β-APP cleaving enzyme 1 (BACE1). These protein–ligand binding free energy calculations illustrate the improvements in conformational sampling and the convergence of the free energy compared to both AIM and AcclAIM.

Stereo-selective synthesis, structural and antibacterial studies of novel glycosylated β2,3-amino acid analogues

Ten β-lactam derivatives (6a–j) with an O-phenyl group at C-2, a glycoside at C-3 and various substituted phenyl rings on the nitrogen, were formed via a series of reactions starting with the glycoside precursors, functionalizing this to the aldehyde, forming the imines and finally the lactams, which were modified, removing the benzyl group on the glycoside producing a further set of lactams (7a–j) and converting them to the β2,3 amino acids (8a–j) in the final stage of the synthesis. The synthesis and structural elucidation of the three sets of compounds are discussed here. In addition, the crystal structure of 6e is also discussed, which shows the absolute configuration of the molecule to be 2S,3R. The Hirshfeld interactions are calculated to be Cl···H (11.1 %), O···H (8.0 %) and N···H (0.4 %). The reaction mechanism for the formation of the β-lactam is also proposed. The three sets of compounds were evaluated for their antibacterial activity against three gram-positive (Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus) and one gram-negative strain (Escherichia coli). The β2,3-amino acids 8a, 8b and 8h showed good antibacterial activity against all strains with MIC values between 0.17 and 1.44 mM, comparable to the standard ampicillin. All three compounds showed better activity to E. coli than ampicillin. Interestingly, molecular docking to the penicillin-binding protein (PBP 2X) showed the same three compounds 8a, 8b and 8h to have a better MolDock score than ampicillin and the free carboxyl groups in the β-amino acid to bind to Ser337, blocking it from further binding with peptidoglycan for cross-linking and subsequent transpeptidation.

Novel hybrid nocodazole analogues as tubulin polymerization inhibitors and their antiproliferative activity.

We describe the design, synthesis and SAR profiling of a series of novel combretastatin-nocodazole conjugates as potential anticancer agents. The thiophene ring in the nocodazole moiety was replaced by a substituted phenyl ring from the combretastatin moiety to design novel hybrid analogues. The hydroxyl group at the ortho position in compounds 2, 3 and 4 was used as the conformationally locking tool by anticipated six-membered hydrogen bonding. The bioactivity profiles of all compounds as tubulin polymerization inhibitors and as antiproliferative agents against the A-549 human lung cancer cell line were investigated Compounds 1 and 4 showed μM IC50 values in both assays.

Design, synthesis and bioevaluation of novel umbelliferone analogues as potential mushroom tyrosinase inhibitors

A series of umbelliferone analogues were synthesized and their inhibitory effects on the DPPH and mushroom tyrosinase were evaluated. The results showed that some of the synthesized compounds exhibited significant mushroom tyrosinase inhibitory activities. Especially, 2-oxo-2-[(2-oxo-2H-chromen-7-yl)oxy]ethyl-2,4-dihydroxybenzoate (4e) bearing 2,4-dihydroxy substituted phenyl ring exhibited the most potent tyrosinase inhibitory activity with IC50 value 8.96 µM and IC50 value of kojic acid is 16.69. The inhibition mechanism analyzed by Lineweaver–Burk plots revealed that the type of inhibition of compound 4e on tyrosinase was non-competitive. The docking study against tyrosinase enzyme was also performed to determine the binding affinity of the compounds. The compounds 4c and 4e showed the highest binding affinity with active binding site of tyrosinase. The initial structure activity relationships (SARs) analysis suggested that further development of such compounds might be of interest. The statistics of our results endorses that compounds 4c and 4e may serve as a structural template for the design and development of novel tyrosinase inhibitors.

The ratio and topology effects of benzodithiophene donor-benzooxadiazole acceptor fragments on the optoelectronic properties of donor molecules toward solar cell materials.

A series of conjugated donor molecules (DmAnSq where m = 1-4, n = 1-7 while D = benzodithiophene, A = benzooxadiazole and S denotes ethyne spacers between D and A or D and D fragments) with various ratios of D/A fragments and topologies have been designed and investigated for OPV applications. An increase in the ratio of the acceptor fragment with respect to the donor fragment decreases the LUMO energy level and narrows the Eg for the designed molecule. More vertically (C4 and C8 substituted phenyl ring positions) bonded acceptor fragments than linearly (C2 and C6 substituted thiophene ring positions) bonded fragments result in a significant red shift in the maximum absorption wavelength. While, linearly bonded fragments lead to stronger absorption bands. Molecules with D-A-D topology exhibit more significant optical and electronic characteristics than those with D-D topology. All donor molecules (m = 2-4) of the D-A-D type show lower λh values than those of 1 donor containing (DAn) molecules. D-D type molecules show only lower λe values than DAn molecules because of the presence of a second donor fragment. The charge transfer phenomenon is shape dependent. The branched or anisotropic X, H, π, n, and square shaped molecules display higher charge transfer rates than the corresponding linear isomers due to better dimensionality. On the basis of these results, we suggest that designed donor and corresponding matched acceptor molecules have potential to act as promising candidates in solar cell devices.