Series 2a Research Articles

Choosing the Best Design in Surgical Research.

Choosing the Best Design in Surgical Research.

An investigation of the electrical conductivity of different stone mastic asphalt mixtures

In recent years, many studies on the prevention of icing on highways and airports through the use of electrically conductive asphalt pavements have been carried out. However, although electrical conductivity in asphalt mixtures has been extensively investigated, the gradation in conductive stone mastic asphalt (SMA) mixtures has not yet been studied in detail. The main purpose of this study was to investigate, for the first time, the effect of aggregate gradation variation on the electrical resistivity and temperature change of electrically conductive SMA. Samples of conductive SMA were produced using three different aggregate gradations (series 1A, 2A and 8S) and 5 mm long carbon fibres (0.2% by weight) as the conductive component. Marshall mix design was performed on series 1A, 2A and 8S. The samples were tested for volume resistivity, temperature change under constant electrical voltage and ultrasonic pulse velocity and the results were compared. The results showed that a change in aggregate gradation had a significant effect on the electrical conductivity properties of the conductive SMA, with a denser gradation of the SMA mixture leading to higher electrical conductivity.

Coastal environmental changes in Southeast Asia: A study from Quang Nam Province, Central Vietnam

Coastal environments are highly dynamic in nature and are sensitive to natural phenomena such as climate change and anthropogenic activities such as aquaculture or infrastructure development. At the same time, these areas are important in the economic development of the whole country, in which they are situated. Coastal areas in Vietnam are affected by a number of factors, such as climate change, sea level rise, aquaculture, pollution and tourism-related activities. This study investigated the coastal environmental changes in Quang Nam, which is a poorly developed province in Central Vietnam during the 31-year period between 1988 and 2019. For this, we analyzed spaceborne data such as Landsat series and Sentinel 2A, and digital elevation models. The coastal environmental variables analyzed were shoreline changes, changes in overall vegetation and mangrove forests, and the expansion of aquaculture ponds. In order to understand the variations in sea level heights, we analyzed HYCOM data for the period between 1994 and 2014. It has been noted that rapid shoreline erosion occurred along the Cua Dai Beach in recent years and the implementation of soft measures, such as sand bags, helped to reduce shoreline erosion to some extent. The current study also contributes to the global inventory of mangroves as most of the study area was missing in the previously available databases such as the world mangrove atlas.

Type 2 inhibitor leads of human tropomyosin receptor kinase (hTrkA).

In silico virtual screening using the ligand-based ROCS approach and the commercially purchasable compound collection from the ZINC database resulted in the identification of distinctly different and novel acetamide core frameworks with series representatives 1a and 2a exhibiting nanomolar affinity in the kinase domain only hTrkA HTRF biochemical assay. Additional experimental validation using the Caliper technology with either the active or inactive kinase conditions demonstrated the leads, 1a and 2a, to preferentially bind the kinase inactive state. X-ray structural analysis of the kinase domain of hTrkA…1a/2a complexes confirmed the kinase, bind the inhibitor leads in the inactive state and to exhibit a type 2 binding mode with the DFG-out and αC-helix out conformation. The leads also demonstrated sub-micromolar activity in the full length hTrkA cell-based assay and selectivity against the closely related hTrkB isoform. However, the poor microsomal stability and permeability of the leads is suggestive of a multiparametric lead optimization effort requirement for further progression.

Teaching English Pragmatic Features in EFL Context: A Focus on Request Speech Acts

This study attempted to explore the possible impacts of teaching English pragmatic features to Iranian high school students’ use of request speech acts. To this end, a sample of Iranian female high school students (n=50) between 12 to 18 years range of age participated in the study. The students with the same level of proficiency were assigned into two experimental and control groups. The data were collected by administering Multiple-Choice Discourse Completion Test (MDCT) as both the pre and the post-tests. The pragmatic features were selected from the high school English textbooks and the excerpts taken from the Top Notch series (2A, 3A, 2B). With the focus on request speech acts, the control group received conventional instructions whereas the experimental group was exposed to the researchers’ request speech act interventions. After statistical analysis of the findings, the data revealed that teaching pragmatic features has significant impact on the Iranian high school students’ performance on request speech acts. Besides, the overall responses by the experimental group showed that indirect request speech acts were more widely used than direct request speech acts as the sign of social and cultural politeness.

Novel Sulfonated CNN Pincer Ligands for Facile C−H Activation at a Pt(II) Center

AbstractTwo novel sulfonated CNN‐pincer ligands 1b and 1c and the corresponding chloro and aqua complexes K[CNNLPtCl] and CNNLPt(H2O), 3b–3c and 2b–2c, were prepared and fully characterized including single crystal X‐ray diffraction. Along with the previously described complexes 2a and 3a, the derivatives of a CNN pincer ligand 1a, these complexes form a family of structurally similar compounds where the pincer core rigidity increases in the series 2a (3a)<2b (3b)<2c (3c), as deduced from their XRD data. The increased ligand rigidity affects the aqua ligand dissociation energy of the CNNLPt(H2O) complexes, as it follows from DFT calculations and as is reflected in the increased reactivity of the aqua complexes 2a, 2b and 2c in processes that involve aqua ligand loss. Among these processes the formation of the presumed dinuclear complexes CNNL2Pt2 and, importantly, catalytic C−D bond cleavage in C6D6 were studied in 2,2,2‐trifluoroethanol solutions. The C−D bond cleavage reactivity was quantified as the rate of H/D exchange between C6D6 and CF3CH2OH at 80 °C.

Design, synthesis, and SAR study of 3-(benzo[d][1,3]dioxol-5-yl)-N-benzylpropanamide as novel potent synergists against fluconazole-resistant Candida albicans

Based on our previous discovery and SAR study on the lead compounds 7d, 5 and berberine which can significantly enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans, a series of 3-(benzo[d][1,3]dioxol-5-yl)-N-(substituted benzyl)propanamides were designed, synthesized, and evaluated for their in vitro synergistic activity in combination with fluconazole. The series 2a–f were designed by replacing the amide moiety of the lead compound 7d with retro-amide moiety, and compounds 2a and 2b showed more activity than the lead 7d. Furthermore, introducing biphenyl moiety into series 2d–f afforded series 3a–r, most of which exhibited significantly superior activity to the series 2d–f. Especially, compound 3e, at a concentration of 1.0µg/ml, can enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans from 128.0µg/ml to 0.125–0.25µg/ml. A clear SAR of the compounds is discussed.

New polycatenar Schiff bases derived from 1,3,4-thiadiazole: synthesis, mesomorphism and luminescence behaviour

ABSTRACTTwo new series of columnar liquid crystal materials based on tetra- and hexacatenar Schiff bases were synthesised by reaction of 4-aminophenyl-1,3,4-thiadiazole derivatives with terephthalaldehyde (series 2a–f) and with 2,5-thiophenedicarbaldehyde (series 3a–f). The mesomorphic properties of these compounds were studied by differential scanning calorimetry (DSC), polarised optical microscopy (POM) and X-ray diffraction (XRD). The mesomorphic behaviour was found to be dependent on the nature of the central ring (benzene in series 2a–f, thiophene in series 3a–f), on length and on number of alkoxy chains. Both tetra- and hexacatenar compounds in series 2a–f display an enantiotropic hexagonal columnar phase. Whereas, in the case of the series 3, only the tetracatenar Schiff bases (3a, 3c and 3e) display enantiotropic hexagonal columnar mesomorphism, hexacatenar Schiff bases (3b, 3d and 3f) do not show mesomorphic properties. Photophysical studies were realised in solution and in solid state. Also, a thermogravimetric analysis was performed. A fibre obtained from compound 3b was analysed by POM showing that the mesophase is maintained in the fibre.

Synthesis of novel symmetrical tetra- and hexacatenar di-amides containing 1,3,4-thiadiazole units and a study of their mesomorphic and luminescence properties

Novel tetra- and hexacatenar materials based on di-amides derived from 4-aminophenyl-1,3,4-thiadiazole derivatives have been synthesised (series 2a–f, 3a-f and 4a–f) and their mesomorphic properties have been studied by differential scanning calorimetry, polarised optical microscopy and X-ray diffraction. All compounds in series 2a–f and 3a–f display an enantiotropic hexagonal columnar phase. With the exception of 4d and 4f, which are non-mesomorphic, all compounds in series 4a–f display enantiotropic hexagonal columnar mesomorphism. The mesomorphic properties were found to be dependent on the length, number of alkoxy chains attached at the end of the rigid core and on the nature of the central ring (benzene in series 2a–f, thiophene in series 3a–f and cyclohexane in series 4a–f). These compounds also show photoluminescence properties in the visible region. A thermogravimetric analysis was also performed.

Synthesis of novel celecoxib analogues by bioisosteric replacement of sulfonamide as potent anti-inflammatory agents and cyclooxygenase inhibitors

Two series of celecoxib analogues having 1,5-diaryl relationship were synthesized. The key strategy of the molecular design was oriented towards exploring bioisosteric modifications of the sulfonamide moiety of celecoxib. First series (2a–2i) of celecoxib analogues bearing cyano functionality in place of sulfonamide moiety was synthesized by the reaction of appropriate trifluoromethyl-β-diketones (5a–5i) with 4-hydrazinylbenzonitrile hydrochloride (4) in ethanol. Cyano moiety of pyrazoles 2 was then converted into corresponding carbothioamides 3 by bubbling H2S gas in the presence of triethylamine. All the synthesized compounds (2a–2i and 3a–3i) were screened for their in vivo anti-inflammatory (AI) activity using carrageenan-induced rat paw edema assay. COX-1 and COX-2 inhibitory potency was evaluated through in vitro cyclooxygenase (COX) assays. Compounds 2a, 2b, 2c, 2e and 3c showed promising AI activity at 3–4h after the carrageenan injection that was comparable to that of the standard drug indomethacin. Although compounds 3d, 3e and 3f exhibited more pronounced COX-2 inhibition but they also inhibit COX-1 effectively thus being less selective against COX-2. Three compounds 2a, 2f and 3a were found to have a COX profile comparable to the reference drug indomethacin. However 2e, 3b, 3c and 3i compounds were the most potent selective COX-2 inhibitors of this study with 3b showing the best COX-2 profile. In order to better rationalize the action and the binding mode of these compounds, docking studies were carried out. These studies were in agreement with the biological data.

Nicardipine Reverses Vasoactivity Associated with University of Wisconsin Solution in the Rat Peripheral Circulation

Background The rapid uniform delivery of University of Wisconsin solution (UW) to the microcirculation may be compromised by its vasoactivity. Methods In 2 different rodent models, we tested whether UW-mediated vasoconstriction could be reversed with nicardipine. Results In the perfused, splanchnic circulation, intravascular control solutions (lactated Ringers [LR], Hextend [HEX], histidine-tryptophan-ketoglutarate [HTK]) or UW (± nicardipine) evoked pressure changes in 3 protocols (series 1; n = 35). In the cremaster muscle, topical control solutions or UW (± nicardipine) evoked vascular responses measured by video microscopy in 4 protocols (series 2; n = 47). In series 1A, 37°C UW increased perfusion pressure, but there was no change caused by LR, HEX, or HTK. In series 1B, 4°C UW caused a similar, albeit transient, increase. In series 1C, nicardipine reversed 37°C UW-mediated vasoconstriction in a dose-related manner. In series 2A, UW caused a 30%–59% constriction that varied with arteriolar branching order. In series 2B, the recovery from UW-induced vasoconstriction varied with duration of exposure, but nicardipine fully reversed residual vasoconstriction. In series 2C, cold and warm UW were equipotent, near maximal, vasoconstrictors. In series 2D, UW potentiated no-reflow. Conclusion UW causes a potent temperature-independent vasoconstriction by a calcium-mediated mechanism and this effect can be mitigated with nicardipine.

Design, synthesis and antileishmanial in vitro activity of new series of chalcones-like compounds: A molecular hybridization approach

The chalcone-like series 1a–1g was efficiently synthesized from Morita–Baylis–Hillman reaction (52–74% yields). Compounds 1a–1g were designed by molecular hybridization based on the anti-inflammatory drug methyl salicylate (3) and the antileishmanial moiety of the Morita–Baylis–Hillman adducts 2a–2g. The 1a–1g compounds were much more actives than precursor series 2a–2g, for example, IC50=7.65μM on Leishmania amazonensis and 10.14μM on Leishmania chagasi (compound 1c) when compared to IC50=50.08μM on L. amazonensis and 82.29μM on L. chagasi (compound 2c). The IC50 values of compound 3 (228.49μM on L. amazonensis and 261.45μM on L. chagasi) and acryloyl salicylate 4 (108.50μM on L. amazonensis and 118.83μM on L. chagasi) were determined here, by the first time, on Leishmania.

Synthesis, anticonvulsant and neurotoxic activity of some new 2,5-disubstituted-1,3,4-oxadiazoles

Two novel series 2a–2d (2Z)-N-[5-(4-substituted)phenyl-1,3,4-oxadiazol-2-yl]-2-[(2Z)-3,7-dimethylocta-2,6-dien-1-ylidene]hydrazinecarboxamide and 1a–1d 5-(4-substituted)phenyl-N-[(1Z,2Z)-3,7-dimethylocta-2,6-dien-1-ylidene]-1,3,4-oxadiazol-2-amine have been synthesized and screened for their anticonvulsant and neurotoxic activity. After i.p. injection to mice at doses of 30, 100 and 300 mg/kg body weight 2,5-disubstituted-1,3,4-oxadiazole analogues were examined in the maximal electroshock induced seizures (MES) and subcutaneous metrazole (ScMET) induced seizure models in mice. Amongst all the compounds, 1a–1d and 2a–2d, one compound 1a exhibited activity at 100 mg/kg body weight at 0.5 and 4 h in ScMET, respectively. Compound 2b showed anticonvulsant activity at 100 mg/kg without activity in ScMET and neurotoxicity. The neurotoxicity was assessed by rotorod method, and all compounds (except 1a) were found to be safe at maximum administered dose.

Tris[oligo(1,4‐phenylenevinylene)]methylium Dyes

AbstractThe tris[oligo(1,4‐phenylenevinylene)]carbinols 2a–f (n =1–4) and the tris(4‐styrylphenyl)methanes 7a,b have been prepared by Wittig–Horner (3 + 4a–f → 2a–f) and Siegristreactions (5 + 6a,b → 7a,b). The Wittig–Horner reactions in these examples are accompanied by an autoxidation, whereas a reduction occurs in the Siegrist reactions. Compound 2a, the lowest member (n = 1) of the series 2a–d with terminal dialkylamino groups, generates first, on treatment with acids, the methylium dye 2′a, which absorbs far into the NIR region (λmax = 1100 nm). The higher members 2b,c (n = 2,3) of the carbinol series yield by acidic treatment only N‐protonated methylium dyes 2″′b,c. The different behavior is due to a decreasing donor–acceptor interaction with increasing D–A distance. The N‐protonated methylium salts 2″′a–c show long‐wavelength absorptions in the region of the Vis/NIR border. Their values apporach, for increasing numbers n of repeat units, λ∞ = 877 nm. The structures and possible push–pull effects of the salts 2′a and 2″′a–c were studied by NMR and UV/Vis/NIR spectroscopy and compared with the selected model compounds 2e and 7a. The results shed new light on previously published triphenylmethane dyes with extended conjugation. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Design, synthesis, structure–activity relationship, and in vivo activity of azabicyclic aryl amides as α7 nicotinic acetylcholine receptor agonists

A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the α7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed α7 nAChR agonist, PNU-282,987, while maintaining the compound’s other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series ( 1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.

Highly antiproliferative, low-calcemic, side-chain ketone analogs of the hormone 1α,25-dihydroxyvitamin D 3

A series 2a– 4b of seven new side-chain ketone analogs of calcitriol ( 1) have been prepared. Unexpectedly, several of these 24- and 25- tert-butyl ketones, even though lacking the classical side-chain tertiary hydroxyl group, are considerably more antiproliferative in vitro than the hormone calcitriol ( 1) even at physiologically relevant low nanomolar concentrations and are less calcemic than calcitriol ( 1) in vivo. In addition, ketone analog 19-nor- 2a is not significantly less calcemic in vivo than 19-methylene analog 2a.

Synthesis and Fungicidal Activity of Novel 2-Oxocycloalkylsulfonylureas

A series of 2-oxocycloalkylsulfonylureas (2) have been synthesized in a six-step, three-pot reaction sequence from readily available cyclododecanone, cycloheptanone, and cyclohexanone. Their structures were confirmed by IR, 1H NMR, and elemental analysis. The bioassay indicated that some of them possess certain fungicidal activity against Gibberella zeae Petch. In general, compounds containing a 12-membered ring (2A) are more active than those containing a 6- or 7-membered ring (2B, 2C). In the series 2A, the compounds in which R is a disubstituted phenyl or pyrimidyl showed better activity than those in which R is a monosubstituted phenyl or pyrimidyl, and aryl-substituted compounds have somewhat higher activity than those substituted by pyrimidyl. The further bioassay showed that the representative of 2A, 2A15, has good fungicidal activities against not only G. zeae Petch but also Botrytis cinerea Pers, Colletotrichum orbiculare Arx, Pythium aphanidermatum Fitzp, Fusarium oxysporum Schl. f. sp. Vasinfectum, etc.

The effect of 2,2-dicyanovinyl groups as electron acceptors in push–pull substituted oligo(1,4-phenylenevinylene)s

The newly synthesized oligo(1,4-phenylenevinylene) series 2a– d with bis(2-hexyloctyl)amino groups as electron donors and 2,2-dicyanovinyl groups as electron acceptors represents conjugated oligomers with strong push–pull effects. Due to the decrease of the intramolecular charge transfer with increasing numbers of repeat units ( n=1–4), the long-wavelength transition shows a particularly great hypsochromic shift for the extension of the chromophore.

Rational design and synthesis of a novel, selective class of thrombin inhibitors: P1-argininal derivatives incorporating P3P4 quaternary lactam dipeptide surrogates

Abstract SAR and molecular modeling investigations on the potent and selective thrombin inhibitor 1b (CVS 1578) and related serine protease inhibitors led to the design of series 2a–g, featuring quaternary α-amino-α-benzyl-lactam scaffolds that serve as novel P3P4 dipeptide mimics. The design, synthesis, and biological activity of these targets are presented.

Synthesis and reduction of 2,2‐diaryl‐1‐nitroethylenes by using a chiral and a non chiral NADH model in the pyrrolopyridine series

AbstractReduction of 2,2‐diphenyl‐1‐nitroethylene (1) and 2‐(2‐pyridyl)‐2‐phenyl‐1‐nitroethylene (5) is achieved by using the NADH model in the pyrrolopyridine series 2a to give 2,2‐diphenyl‐1‐nitroethane (3) and 2‐(2‐pyridyl)‐2‐phenyl‐1‐nitroethane (7) respectively in 40% yield. The asymmetric reduction of 2‐(2‐pyridyl)‐2‐phenyl‐1‐nitroethylene by the chiral NADH model 2b is studied. Thus, 2‐(2‐pyridyl)‐2‐phenyl‐1‐nitroethane (7) is obtained in 15 to 32% yield. The stereocontrol of the reduction proved to be dependent on the amount of magnesium ions.